None listed
Conditions
Brief summary
Overactive sympathetic nervous system (SNS) signaling to major metabolic organs plays a pivotal role in the development & progression of Metabolic Syndrome (MetS) into several concurrent cardiometabolic disorders. Given the close relationship between the MetS & overactive SNS signaling, a minimally invasive treatment approach targeting inhibition of SNS to central metabolic organs (kidney & liver) is being proposed. The objective is to evaluate the safety of hepatic or renal artery denervation or a combination of both in a single intravascular procedure intended to improve one or more cardiometabolic parameters for hypertension (HTN) & glycaemic control. 45 patients with HTN with coexistent type-2 diabetes who qualify & consent, will be assigned to one of the 3 arms.
Interventions
The iRF System is a percutaneous, catheter-based device which uses RF energy to circumferentially ablate the sympathetic nerves surrounding the Common Hepatic Artery (CHA) while minimizing injury to the arterial wall. The iRF System consists of the following components:
1. Single-use, monopolar, Ablation Catheter that contains four (4) electrodes; provided sterile
2. Reusable, Radiofrequency Generator (RFG) with an Integrated Syringe Pump
3. Single-use, Generator Accessory Kit that contains a Sy
The iRF System is a percutaneous, catheter-based device which uses RF energy to circumferentially ablate the sympathetic nerves surrounding the Common Hepatic Artery (CHA) while minimizing injury to the arterial wall. The iRF System consists of the following components: 1. Single-use, monopolar, Ablation Catheter that contains four (4) electrodes; provided sterile 2. Reusable, Radiofrequency Generator (RFG) with an Integrated Syringe Pump 3. Single-use, Generator Accessory Kit that contains a Syringe Cassette, two (2) tubing sets, and a waste collection bag, provided sterile This procedure will be completed by an Interventional Cardiologist/Radiologist that has been trained on the device. It will occur in a catheterization laboratory or appropriate surgical setting. Up to 4 ablations will be administered during one procedure which will last no more than 2 hours. Clinical observation and monitoring by the treating physician of the iRF system will be conducted throughout the procedure. The generator will also display system progress. Each denervation cycle will provide energy for 150 seconds to the target artery. Patients will be assigned to one of the 3 treatment arms: • Renal denervation arm (RDN) - denervation procedure completed in the left and right renal arteries • Hepatic denervation arm (HDN) - denervation procedure completed in the common hepatic artery • Multi-organ (liver and kidney) denervation arm (MDN) - denervation procedure completed in the common hepatic artery, left renal artery, and right renal artery. The study management team (Metavention) will review to confirm eligibility and will allocate treatment as follows. • After the baseline visit, if the subject remains eligible based on all the inclusion/exclusion criteria (1-65), the study centre will complete a request for assignment. The patient will be preferentially assigned to the multi-organ treatment arm (if anatomically suitable), until such time that arm has reached its cap of 15 subjects. Subsequent assignments can then be made to the remaining single organ treatment arms until enrolment is complete. • At the screening and baseline visit, if the subject meets eligibility criteria 1-56 for the study, but only the renal arteries are found to be suitable (criteria 57-65), the patient will be assigned to the RDN arm. The treatment assignment will be documented, and a copy returned to site for the subject file. • At the screening and baseline visit, if the subject meets eligibility criteria 1-56 for the study, but only the hepatic artery is found to be suitable (criteria 57-65), AND if the patient has been enrolled as drug naïve, the patient will be assigned to the HDN arm. The treatment assignment will be documented, and a copy returned to the site for the subject file.
Sponsors
Metavention, Inc.
Study design
Allocation
Non-randomised trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject)
Eligibility
Sex/Gender
All
Age
22 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1) Age greater than or equal to 22 and less than or equal to 70 years old 2) Type 2 Diabetes diagnosis meeting the following criteria: a) On oral anti-diabetic (OAD) medication: Hb1A1c 58 mmol/mol – 97 mmol/mol (7.5% - 11%), AND on a consistent drug regimen of oral anti diabetic agents (i.e., metformin, SGLT-2 inhibitor) or injectables (GLP 1-Ra) for at least 90 days prior to screening OR b) Medication naïve subjects at screening (off any medications for diabetes for at least 90- days): HbA1c 53 mmol/mol – 86 mmol/mol (7% - 10%) 3) Diagnosis of Hypertension meeting one of the following screening criteria AND baseline criteria: a) Subjects on antihypertension medication at screening: Office Systolic BP greater than or equal to 130 mmHg and less tahn 180 mmHg based on an average of 3 automated office blood pressure (AOBP) readings, AND on a consistent regimen of 1 - 2 antihypertensive medications (monotherapy or combination pills) or up to 3 oral antihypertensive agents (ARBs, CCBs, ACE inhibitors, hydrochlorothiazide etc.) for at least 4 weeks prior to screening OR b) Medication naïve subjects at screening (off any medications for hypertension for at least 28- days prior to screening): Office Systolic BP greater than or equal to 140 mmHg and less tahn 180 mmHg based on an average of 3 automated office blood pressure (AOBP) readings. AND c) Subjects at Baseline (not on medication): Systolic daytime BP greated than or equal to 135 mmHg and less than 170 mmHg based on baseline ABPM 4) Waist circumference criteria greater than or equal to 102 cm (male) and greater than or equal to 88cm (female) i) Asians: greater than or equal to 90 cm (male) and greater than or equal to 80 cm (female) 5) Willing and able to discontinue all anti-hypertensive medications through 90-day follow-up visit 6) Documented status of stable lifestyle modifications 7) Women of childbearing potential (WOCBP) must be using at least one acceptable method of contraception throughout the study
Exclusion criteria
8) BMI >40 kg/m2 9) Diagnosis of type 1 diabetes 10) Use of insulin within 90 days of consent 11) Two or more self-reported or documented severe hypoglycaemia events (severe hypoglycaemia event defined as severe cognitive impairment requiring external assistance for recovery) in the 180 days prior to Screening or any hypoglycaemia event from the time of Screening until Index Procedure 12) One or more documented hyperglycaemia episodes requiring hospitalization in the 180-days prior to Index Procedure 13) Severe hyperglycaemia event (confirmed by 2 consecutive fasting plasma glucose levels >240mg/dL) from time of Screening until Index Procedure 14) Current use of >2 antihypertension medications (monotherapy or combination pills) or >3 oral antihypertensive agents (ARBs, CCBs, ACE inhibitors, hydrochlorothiazide etc.) 15) Prescribed to any standard antihypertensive of cardiovascular medication (e.g., beta blockers) for other chronic conditions (e.g., ischemic heart disease) such that discontinuation might pose serious risk to health 16) Severe hypertensive episode within 180 days prior to the Index Procedure (confirmed by 3 Office Systolic BP measurements of greater than or equal to 180 mmHg) 17) A history of bariatric surgery, baroreflex activation therapy, or liver transplant, or these procedures are planned in the 365 days following Index Procedure 18) Any surgical procedure within 30 days prior to Index Procedure 19) Previous renal denervation procedure 20) History of or current symptomatic gallstones (e.g., cholecystitis, bile duct dilatation) without a cholecystectomy being performed (Note: subjects who have had a cholecystectomy are not excluded) 21) Previous hepatobiliary surgery/intervention that in the opinion of the investigator could preclude the ability to perform denervation of the CHA 22) Currently taking the following medications within 90 days prior to screening and/or there is a need or anticipated need for these medications during the study: a) Systemic Corticosteroids b) Anticonvulsants c) Centrally acting sympatholytics (other than for treatment of hypertension) 23) Use of anticoagulation therapy which cannot be discontinued from 7 days before to 14 days after the Index Procedure 24) Any other condition(s) that would compromise the safety of the subject or compromise study quality as judged by the Investigator 25) eGFR <45 mL/min/1.73 m2 26) History or diagnosis of proliferative retinopathy or advanced autonomic neuropathy (e.g., orthostatic hypotension attributable to autonomic neuropathy, a diagnosis of gastroparesis, or a clinical history strongly suggestive of delayed gastric emptying) 27) Myocardial infarction, unstable angina, stroke, or transient ischemic attack within the 180 days prior to Index Procedure, or has widespread atherosclerosis, with documented intravascular thrombosis or unstable plaques 28) Subject has any of the following conditions: severe cardiac valve stenosis, heart failure (New York Heart Association [NYHA] Class III or IV), chronic atrial fibrillation, and known primary pulmonary hypertension (>60 mmHg pulmonary artery or right ventricular systolic pressure). 29) Documented history or concurrent signs of significant thyroid disease NOTE: If a subject is on chronic thyroid drug treatment, and has a serum TSH test result in normal range at Baseline they may enter study 30) Uncorrectable bleeding diathesis, platelet dysfunction, thrombocytopenia with platelet count <100,000/microliter, or documented coagulopathy 31) Subject is being treated chronically (e.g., daily use) with immunosuppressive medications or immunosuppressive doses of steroids. Nasal pulmonary inhalants are allowed. 32) Chronic regular use (e.g., daily use) of NSAIDs for 6 months or greater. Aspirin therapy is allowed. 33) Evidence of active infection within 7 days prior to the Index Procedure 34) Significant alcohol consumption, defined as more than 2 drink units per day (equivalent to 20 g) in women and 3 drink units per day (equivalent to 30 g) in men, or inability to reliably quantify alcohol intake 35) Active substance abuse, based on Investigator judgment, including inhaled or injected drugs, within 1 year prior to the initial screening 36) Uncontrolled or severe depression 37) Significant weight loss within the last 6 months (e.g., >10% total body weight loss) 38) Hepatic decompensation defined as the presence of any of the following: a) Serum albumin less than 3.5 g/dL b) International normalized ratio (INR) greater than 1.4 (unless due to therapeutic anticoagulants) c) Total bilirubin greater than 2 mg/dL with the exception of Gilbert syndrome d) History of oesophageal varices, ascites, or hepatic encephalopathy 39) ALT or AST greater than 200 U/L 40) Diagnosis of liver cirrhosis 41) Chronic liver or biliary disease of the following aetiology: a) History or evidence of Hepatitis B b) History or evidence of Hepatitis C c) History or evidence of current active autoimmune hepatitis d) History or evidence of primary biliary cholangitis (PBC) e) History or evidence of primary sclerosing cholangitis f) History or evidence of Wilson's disease g) History or evidence of alpha-1-antitrypsin deficiency h) History or evidence of hemochromatosis i) History or evidence of drug-induced liver disease, as defined on the basis of typical exposure and history j) Known bile duct obstruction k) Suspected or proven liver cancer 42) History of acute or chronic pancreatitis 43) Subjects unable to undergo CT for any reasons 44) Currently enrolled in any other investigational trial 45) History of epilepsy or seizures 46) Iliac/femoral artery stenosis preventing the procedure from being performed 47) Human immunodeficiency virus (HIV) 48) Subjects with a history of adverse reaction to heparin or heparin induced thrombocytopenia (HIT) 49) Subjects with conditions that can affect RBC turnover, those who have received a blood transfusion in the past 90 days, or expect to have an elective procedure during the course of the study that may require blood transfusion 50) Not a candidate for surgery or general anaesthesia 51) Currently works night shifts 52) Unwilling to comply with study requirements, including medication washout, SMBG, patient diary and follow-up visits Anatomic Exclusions from CT Angiogram 53) Replaced or accessory LHA or RHA determined on CT angiogram. 54) A single functioning kidney 55) Presence of abnormal kidney (or secreting adrenal) tumours 56) Renal artery with aneurysm 57) Pre-existing stent or history of angioplasty in target arteries 58) Fibromuscular dysplasia of the renal arteries 59) Evidence of median arcuate ligament syndrome (MALS) 60) Vessel tortuosity or variant vascular anatomy that could preclude the access or manoeuvring of the device from the femoral artery to the target locations 61) Evidence of intraluminal thrombus 62) Accessory arteries with diameter greater than or equal to 3mm and <4mm 63) CHA or RA vessel diameter <4.0mm or >7.0mm 64) CHA or RA diameter stenosis >30% 65) CHA or RA vessel length <20mm
Outcome results
None listed