Trial Review

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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
24/06/2022
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 Reduce 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 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.
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

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: 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
Minimum age
22 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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 assigned to one of the 3 treatment arms:
• 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
Recruiting
Date of first participant enrolment
Anticipated
16/03/2021
Actual
16/03/2021
Date of last participant enrolment
Anticipated
1/04/2023
Actual
Date of last data collection
Anticipated
1/04/2024
Actual
Sample size
Target
45
Accrual to date
12
Final
Recruitment in Australia
Recruitment state(s)
NSW,WA,VIC
Recruitment hospital [1] 15704 0
The Alfred - Melbourne
Recruitment hospital [2] 15705 0
Royal Perth Hospital - Perth
Recruitment hospital [3] 18823 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [4] 21416 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [5] 22602 0
Sydney Southwest Private Hospital - Liverpool
Recruitment postcode(s) [1] 29125 0
3004 - Melbourne
Recruitment postcode(s) [2] 29126 0
6000 - Perth
Recruitment postcode(s) [3] 33273 0
3084 - Heidelberg
Recruitment postcode(s) [4] 36308 0
3168 - Clayton
Recruitment postcode(s) [5] 37861 0
2170 - Liverpool

Funding & Sponsors
Funding source category [1] 304806 0
Commercial sector/Industry
Name [1] 304806 0
Metavention, Inc.
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
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
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
[email protected]
Contact person for public queries
Name 99663 0
Adam Ahlstrom
Address 99663 0
Adam Ahlstrom, Clinical Director, Metavention, Inc. 10900 73rd Avenue North Suite 101 Maple Grove, MN 55369
Country 99663 0
United States of America
Phone 99663 0
+1 6128148208
Fax 99663 0
Email 99663 0
[email protected]
Contact person for scientific queries
Name 99664 0
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
[email protected]

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 Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.