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Trial registered on ANZCTR


Registration number
ACTRN12620000412932
Ethics application status
Approved
Date submitted
30/01/2020
Date registered
27/03/2020
Date last updated
12/05/2020
Date data sharing statement initially provided
27/03/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Evaluation of the Integrated Radio Frequency Denervation System to RedUuce Sympathetic Drive
Scientific title
Multi-Organ Denervation to RedUce Sympathetic Drive, A Single Blinded, Multi-Center, Prospective Feasibility Study
Secondary ID [1] 300385 0
None
Universal Trial Number (UTN)
Trial acronym
MODUS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hypertension 316006 0
Type 2 Diabetes 316007 0
Condition category
Condition code
Cardiovascular 314278 314278 0 0
Hypertension
Metabolic and Endocrine 314279 314279 0 0
Diabetes

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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 randomised to one of the 3 treatment arms (1:1:1):
• 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.
Intervention code [1] 316667 0
Treatment: Devices
Comparator / control treatment
There are three different treatment groups in this study
Control group
Active

Outcomes
Primary outcome [1] 322670 0
The incidence rate of device related serious adverse device effects (SADEs) from time of Index Procedure through 90 days. Some potential adverse events include but are not limited to: post operative pain, hematoma at the access site, tenderness and swelling at the catheter insertion site, allergic reaction to materials used, high or low blood pressure or damage to the liver. All events will be assessed using a variety of methods including: monitoring of vital signs, blood labs, glucose testing, imaging and self-reporting. Patients will be closely monitored by the study physician throughout study participation
Timepoint [1] 322670 0
90 days
Secondary outcome [1] 379241 0
Change in Ambulatory Blood Pressure (ABP) using ambulatory blood pressure monitor, worn for at least 24 hours at each time-point.
Timepoint [1] 379241 0
30, 90, 180 and 365 days post index procedure
Secondary outcome [2] 379242 0
Change in Office Blood Pressure assessed while in the physicians office using their standard automated office blood pressure (AOBP) method of assessing blood pressure with a sphygmomanometer.
Timepoint [2] 379242 0
30, 90, 180 and 365 days post index procedure
Secondary outcome [3] 379243 0
Glyceamic control will be measured through blood labs of: HbA1c
Timepoint [3] 379243 0
30, 90, 180 and 365 days post index procedure
Secondary outcome [4] 379244 0
Change in Mixed Meal Tolerance Test
Timepoint [4] 379244 0
30, 90, 180 and 365 days post index procedure
Secondary outcome [5] 379245 0
Change in liver steatosis using MRI-PDFF
Timepoint [5] 379245 0
90 and 365 days post index procedure

Eligibility
Key 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: Hb1Ac 48 mmol/mol – 69 mmol/mol (6.5% - 8.5%), AND
b) On a consistent drug regimen up to 2 OAD medications (i.e., metformin, SGLT-2 inhibitor) for at least 90 days prior to baseline
3) Diagnosis of Hypertension meeting the following criteria:
a) Subjects on drugs: Office Systolic BP greater than or equal to 140 mmHg based on an average of 3 automated office blood pressure (AOBP) readings, AND
b) Subjects after washout: Systolic daytime BP greater than or equal to 140 mmHg based on baseline ABPM
c) On a consistent regimen of 1 -2 antihypertensive medications for at least 90 days prior to baseline
4) MRI-PDFF greater than or equal to 10% indicating NAFLD
5) Waist circumference criteria:
a) Caucasians: greater than or equal to 102 cm (male) and greater than or equal to 88cm (female)
b) Asians: greater than or equal to 90 cm in men and greater than or equal to 80 cm in women
6) Willing and able to discontinue all OAD and anti-hypertensive medications through 90-day follow-up visit
7) Documented status of stable lifestyle modifications
8) Women of childbearing potential (WOCBP) must be using at least one acceptable method of contraception throughout the study
Minimum age
22 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
9) BMI >40 kg/m2
10) Diagnosis of type 1 diabetes
11) Current or history of injectable diabetic medication use (i.e., insulin or GLP-1RA)
12) 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
13) One or more documented hyperglycaemia episodes requiring hospitalization in the 180-days prior to Index Procedure
14) Severe hyperglycaemia event (confirmed by 2 consecutive fasting plasma glucose levels >240mg/dL) from time of Screening until Index Procedure
15) Current use of >2 antihypertension medications
16) 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
17) Severe hypertensive episode within 180 days prior to the Index Procedure (confirmed by 3 Office Systolic BP measurements of = 180 mmHg)
18) A history of bariatric surgery, baroreflex activation therapy, or liver transplant, or these procedures are planned in the 365 days following Index Procedure
19) Any surgical procedure within 30 days prior to Index Procedure
20) Previous renal denervation procedure
21) History of gallstones without a cholecystectomy being performed or current gallstones (Note: subjects who have had a cholecystectomy are not excluded)
22) Previous hepatobiliary surgery/intervention that in the opinion of the investigator could preclude the ability to perform denervation of the CHA
23) 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)
24) Use of anticoagulation therapy which cannot be discontinued from 7 days before to 14 days after the Index Procedure
25) Any other condition(s) that would compromise the safety of the subject or compromise study quality as judged by the Investigator
26) eGFR <45 mL/min/1.73 m2
27) 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)
28) 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
29) 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).
30) 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
31) Uncorrectable bleeding diathesis, platelet dysfunction, thrombocytopenia with platelet count <100,000/microliter, or documented coagulopathy
32) Subject is being treated chronically (e.g. daily use) with immunosuppressive medications or immunosuppressive doses of steroids. Nasal pulmonary inhalants are allowed.
33) Chronic regular use (e.g. daily use) of NSAIDs for 6 months or greater. Aspirin therapy is allowed.
34) Evidence of active infection within 7 days prior to the Index Procedure
35) 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
36) Active substance abuse, based on Investigator judgment, including inhaled or injected drugs, within 1 year prior to the initial screening
37) Uncontrolled or severe depression
38) Significant weight loss within the last 6 months (e.g., >10% total body weight loss)
39) 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
40) ALT or AST greater than 200 U/L
41) Diagnosis of liver cirrhosis
42) 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
43) History of acute or chronic pancreatitis
44) Subjects unable to undergo MRI-PDFF or CT for any reasons
45) Currently enrolled in any other investigational trial
46) History of epilepsy or seizures
47) Iliac/femoral artery stenosis preventing the procedure from being performed
48) Human immunodeficiency virus (HIV)
49) Subjects with a history of adverse reaction to heparin or heparin induced thrombocytopenia (HIT)
50) 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
51) Not a candidate for surgery or general anaesthesia
52) Currently works night shifts
53) Unwilling to comply with study requirements, including medication run-in, SMBG, patient diary and follow-up visits
Anatomic Exclusions from CT Angiogram
54) Replaced or accessory LHA or RHA determined on CT angiogram.
55) A single functioning kidney
56) Presence of abnormal kidney (or secreting adrenal) tumours
57) Renal artery with aneurysm
58) Pre-existing stent or history of angioplasty in target arteries
59) Fibromuscular disease of the renal arteries
60) Evidence of median arcuate ligament syndrome (MALS)
61) Vessel tortuosity or variant vascular anatomy that could preclude the access or manoeuvring of the device from the femoral artery to the target locations
62) Evidence of intraluminal thrombus
63) Accessory arteries with diameter greater than or equal to 2mm
64) CHA or RA vessel diameter <4.0mm or >7.0mm
65) CHA or RA diameter stenosis >30%
66) CHA or RA vessel length <20mm

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
central randomisation by phone/fax/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Parallel
Other design features
Subjects will be blinded to which treatment arm they are assigned. A total of 45 patients will be randomised to one of the 3 treatment arms (1:1:1):
• Renal denervation arm (RDN)
• Hepatic denervation arm (HDN)
• Multi-organ (liver and kidney) denervation arm (MDN)
Phase
Not Applicable
Type of endpoint(s)
Statistical methods / analysis
Descriptive summaries will be the basis of study reports to generate an overall summary of the safety and clinical performance of the device. Continuous outcome variables will be presented as means and standard deviations with 95% confidence intervals, as well as medians and ranges. For categorical outcome variables, relative frequencies will be provided. Descriptive tables will be produced for baseline characteristics including demographics, medical history, procedure, adverse events, medications, physical exams, protocol deviations, laboratory assessments and outcomes.

Statistical analyses will be performed using SAS/STAT software, Version 9.4 or higher of the SAS System for Windows. Additional analyses may be performed using R Version 3.6.0 or higher.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA,VIC
Recruitment hospital [1] 15704 0
The Alfred - Melbourne
Recruitment hospital [2] 15705 0
Royal Perth Hospital - Perth
Recruitment postcode(s) [1] 29125 0
3004 - Melbourne
Recruitment postcode(s) [2] 29126 0
6000 - Perth

Funding & Sponsors
Funding source category [1] 304806 0
Commercial sector/Industry
Name [1] 304806 0
Metavention, Inc.
Address [1] 304806 0
10900 73rd Avenue North
Suite 101
Maple Grove, MN 55369
Country [1] 304806 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Metavention, Inc.
Address
10900 73rd Avenue North
Suite 101
Maple Grove, MN 55369
Country
United States of America
Secondary sponsor category [1] 305129 0
Commercial sector/Industry
Name [1] 305129 0
Mobius Medical Pty Ltd
Address [1] 305129 0
Suite 401
275 Alfred Street
North Sydney NSW 2060
Country [1] 305129 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305221 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 305221 0
55 Commercial Road
Melbourne, VIC 3004
Ethics committee country [1] 305221 0
Australia
Date submitted for ethics approval [1] 305221 0
20/01/2020
Approval date [1] 305221 0
05/03/2020
Ethics approval number [1] 305221 0
HREC/60968/Alfred-2020

Summary
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 randomised to one of the 3 arms (1:1:1).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 99662 0
Dr Markus Schlaich and Gerard Goh
Address 99662 0
Markus Schliach: Royal Perth Hospital
The University of Western Australia
Level 3, MRF Building, Rear 50 Murray St
PERTH WA 6000

Gerard Goh: Alfred Health
55 Commercial Road
Melbourne VIC 3004
PO Box 315 Prahran
VIC 3181 Australia
Country 99662 0
Australia
Phone 99662 0
+61 8 9224 0382
Fax 99662 0
Email 99662 0
markus.schlaich@uwa.edu.au
Contact person for public queries
Name 99663 0
Mrs Megan Brandt
Address 99663 0
Megan Brandt SVP of regulatory affairs
Metavention, Inc.
10900 73rd Avenue North
Suite 101
Maple Grove, MN 55369
Country 99663 0
United States of America
Phone 99663 0
+1 6128148204
Fax 99663 0
Email 99663 0
mbrandt@metavention.com
Contact person for scientific queries
Name 99664 0
Prof Markus Schlaich
Address 99664 0
Royal Perth Hospital Unit
The University of Western Australia
Level 3, MRF Building, Rear 50 Murray St, PERTH WA 6000
Country 99664 0
Australia
Phone 99664 0
+61 8 9224 0382
Fax 99664 0
Email 99664 0
markus.schlaich@uwa.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results