Re-Shape: Renal Sympathetic Denervation and Potential Effects on Glucose Metabolism and Cardiovascular Risk-Factors

Sponsor

University Hospital of North Norway (Other)

Overall Status

Completed

CT.gov ID

NCT01630928

Collaborator

University of Tromso (Other), The Royal Norwegian Ministry of Health (Other), Odd Berg Medical research Foundation (Other)

Enrollment

Location

Arm

Duration (Months)

1.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The Re-Shape CV-Risk Study is a clinical study where renal adrenergic denervation (RDN) is done in high risk patients with treatment-resistant hypertension. RDN is a mini-invasive, percutaneous technique where an ablation catheter is inserted through a femoral artery into the renal arteries, for destruction of the adrenergic nerve bundles in the artery adventitia by means of radio-frequency ablation. RDN leads to sympathetic denervation of the kidneys, which in the "Symplicity trials" led to an impressive reduction of blood pressure (- 33 /-11 mmHg). In a pilot study, where 40 % of the patients had diabetes, RDN seemed to have beneficial effects not only on blood pressure, but also on insulin sensitivity and hyperinsulinaemia.

The investigators aim to introduce RDN as a clinical study where blood pressure reduction and methodical, technical aspects will be evaluated, but more importantly, also additional effects of RDN on sub-clinical organ damage (endothelial function, vascular stiffness, fundus-, heart-, kidney injury), quality of life, arrhythmia, and glucose metabolism. The investigators hypothesis is that RDN will have positive effect on glucose metabolism, QOL and sub-clinical organ damage.

Condition or Disease	Intervention/Treatment	Phase
Hypertension, Resistant to Conventional Therapy	Procedure: Renal sympathetic denervation	N/A

Study Design

Study Type:

Interventional

Actual Enrollment :

50 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Renal Sympathetic Denervation for Treatment Resistant Hypertension and Potential Effects on Glucose Metabolism and Cardiovascular Risk-Factors (The Re-Shape CV-Risk Study)

Study Start Date :

Mar 1, 2013

Actual Primary Completion Date :

Dec 1, 2015

Actual Study Completion Date :

Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Renal sympathetic denervation Patients with treatment resistant hypertension	Procedure: Renal sympathetic denervation This is a mini-invasive trans-catheter procedure with access via a 6F introducer in one of the femoral arteries. The renal sympathetic nerves arise from T10-L2, arborize around the renal artery and primarily lie within the adventitia. A specialized radiofrequency (RF) ablation catheter is introduced into the renal arteries, first one side, then on the other. Usually, 4-6 two-minute treatments per artery using a proprietary RF generator with automated low power and built-in safety algorithms are sufficient to ablate the sympathetic afferent and efferent fibers. Other Names: Symplicity Catheter (Medtronic)

Arm

Intervention/Treatment

Experimental: Renal sympathetic denervation

Patients with treatment resistant hypertension

Procedure: Renal sympathetic denervation

This is a mini-invasive trans-catheter procedure with access via a 6F introducer in one of the femoral arteries. The renal sympathetic nerves arise from T10-L2, arborize around the renal artery and primarily lie within the adventitia. A specialized radiofrequency (RF) ablation catheter is introduced into the renal arteries, first one side, then on the other. Usually, 4-6 two-minute treatments per artery using a proprietary RF generator with automated low power and built-in safety algorithms are sufficient to ablate the sympathetic afferent and efferent fibers.

Other Names:

Symplicity Catheter (Medtronic)

Outcome Measures

Primary Outcome Measures

Change in blood pressure [from baseline to six months]
Change in blood pressure from baseline to six months after the intervention
Change in blood pressure [from baseline to two years]
Change in blood pressure from baseline to two years after the intervention

Secondary Outcome Measures

Change in quality of Life [From baseline to six months]
The international questionnaires SF-36 and 15-D, with some additional specific questions previously used in international studies will be used for evaluation of RDN effect on symptoms and QOL.
Changes in glucose production and insulin sensitivity [from baseline to six months]
Glucose metabolism will be assessed with oral glucose tolerance test and 2-step euglycemic, hyperinsulinaemic clamp with tracer technique (6,6-2H2-glucose + HOTGINF / measurement of tracer-to-tracee ratio with mass spectrometry): Assessment of endogenous glucose production at fasting condition, at insulin levels around 30 mU/ml (hepatic insulin sensitivity), and at insulin levels of 65-68 mU/ml, imitating the postprandial state (peripheral insulin resistance). Assessment of glucose uptake at these conditions (insulin sensitivity).
Change in quality of Life [From baseline to two years]
The international questionnaires SF-36 and 15-D, with some additional specific questions previously used in international studies will be used for evaluation of RDN effect on symptoms and QOL.
Changes in glucose production and insulin sensitivity [from baseline to two years]
Glucose metabolism will be assessed with oral glucose tolerance test and 2-step euglycemic, hyperinsulinaemic clamp with tracer technique (6,6-2H2-glucose + HOTGINF / measurement of tracer-to-tracee ratio with mass spectrometry): Assessment of endogenous glucose production at fasting condition, at insulin levels around 30 mU/ml (hepatic insulin sensitivity), and at insulin levels of 65-68 mU/ml, imitating the postprandial state (peripheral insulin resistance). Assessment of glucose uptake at these conditions (insulin sensitivity).
Effect of RDN on subclinical organ injury: Myocardium [from baseline to six months]
Long standing hypertension leads to sub-clinical organ damage: Myocardial and vascular remodeling measured with echo cardiography. Wall stiffness, left ventricular function, hypertrophy and mass.
Effect of RDN on subclinical organ injury: Myocardium [from baseline to two years]
Long standing hypertension leads to sub-clinical organ damage: Myocardial and vascular remodeling measured with echo cardiography. Wall stiffness, left ventricular function, hypertrophy and mass.
Effect of RDN on subclinical organ injury: Retinal vessels [from baseline to six months]
Long standing hypertension leads to sub-clinical organ damage: Changes in the microcirculatory vasculature detectable as early changes in retinal vascular caliber or presence of hypertensive retinopathy. High resolution photography (Carl Zeiss Meditec.) and optic coherence tomography of the retina give a direct view to microcirculation. Analyzes will be performed using computer assisted morphometry (IVAN/Retinal Analysis software. Fundus Reading center, University of Wisconsin, Madison USA).
Effect of RDN on subclinical organ injury: Retinal vessels [from baseline to two years]
Long standing hypertension leads to sub-clinical organ damage: Changes in the microcirculatory vasculature detectable as early changes in retinal vascular caliber or presence of hypertensive retinopathy. High resolution photography (Carl Zeiss Meditec.) and optic coherence tomography of the retina give a direct view to microcirculation. Analyzes will be performed using computer assisted morphometry (IVAN/Retinal Analysis software. Fundus Reading center, University of Wisconsin, Madison USA).
Effect of RDN on subclinical organ injury: Kidneys [from baseline to six months]
Long standing hypertension leads to sub-clinical organ damage: Renal dysfunction. We will measure serum creatinine, cystatin C, GFR (iohexol clearance), albumine/creatinine ratio and N-Acetyl-ß-glucosaminidase (NAG) in morning urine (two different days) before and after RDN. NAG excretion is a sign of tubular injury.
Effect of RDN on subclinical organ injury: Kidneys [from baseline to two years]
Long standing hypertension leads to sub-clinical organ damage: Renal dysfunction. We will measure serum creatinine, cystatin C, GFR (iohexol clearance), albumine/creatinine ratio and N-Acetyl-ß-glucosaminidase (NAG) in morning urine (two different days) before and after RDN. NAG excretion is a sign of tubular injury.
Effect of RDN on subclinical organ injury: Endothelial function [from baseline to six months]
Long standing hypertension leads to sub-clinical organ damage: Impaired endothelial function; assessed with plethysmography under reactive hyperemia + markers of endothelial dysfunction; Peripheral vasodilator function is measured by digital pulse amplitude tonometry using EndoPAT 2000 (Itamar Medical Ltd., Caesarea, Israel). Reactive hyperemia is produced by applying a blood pressure cuff for 5 min at a pressure of 60 mmHg higher than the systolic pressure on the upper part of the arm.
Effect of RDN on subclinical organ injury: Endothelial function [from baseline to two years]
Long standing hypertension leads to sub-clinical organ damage: Impaired endothelial function; assessed with plethysmography under reactive hyperemia + markers of endothelial dysfunction; Peripheral vasodilator function is measured by digital pulse amplitude tonometry using EndoPAT 2000 (Itamar Medical Ltd., Caesarea, Israel). Reactive hyperemia is produced by applying a blood pressure cuff for 5 min at a pressure of 60 mmHg higher than the systolic pressure on the upper part of the arm.
Effect of RDN on subclinical organ injury: Impedance cardiography [from baseline to two years]
Increased central blood pressure measured in ascending aorta, in addition to "augmentation index" (peak aortic pressure increase/pulse pressure) as a measure of vessel compliance, are independent predictors for hypertensive organ injury (brain, heart, kidneys). Aortic wall-stiffness (compliance) and pulse wave reflection are important determinants for central blood pressure and are among the parameters we indirectly will get from impedance cardiography (Hotman System, HEMO SAPIENS INC, Bucharest, Romania)
Effect of RDN on subclinical organ injury: Impedance cardiography [from baseline to six months]
Increased central blood pressure measured in ascending aorta, in addition to "augmentation index" (peak aortic pressure increase/pulse pressure) as a measure of vessel compliance, are independent predictors for hypertensive organ injury (brain, heart, kidneys). Aortic wall-stiffness (compliance) and pulse wave reflection are important determinants for central blood pressure and are among the parameters we indirectly will get from impedance cardiography (Hotman System, HEMO SAPIENS INC, Bucharest, Romania)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥ 18 Years.
Resistant hypertension, as defined in the 2007 ESH-ESC guidelines and confirmed by ambulatory or home blood pressure measurements. (Here office BP > 140/90 mmHg on 4 or more antihypertensive drugs in adequate dosages (including one diuretic) or certified drug intolerance).
No known secondary reason for hypertension
Negative pregnancy test (preferably blood hCG) for female patients of childbearing potential
Estimated GFR (glomerular filtration rate) > 45 mL/min/1.73m².
Willing and able to comply with follow-up requirements
Signed informed consent

Exclusion Criteria:

Type 1 and type 2 diabetes
Pregnancy
Allergy to the contrast medium used during RDN and Iohexol clearance.
Age > 68 years
Hemodynamically significant heart valve disease
Pacemaker or ICD
Medication that may interfere with the procedure (Anticoagulation, Platelet inhibitors, Steroids), if they cannot be temporarily reduced or stopped.
Cancer
Patients with transplanted kidneys
Reno vascular conditions like diameter < 4mm, renal artery stenosis or significant atherosclerosis, previous renal artery stenting

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University Hospital of North Norway	Tromsø		Norway	N-9038

Sponsors and Collaborators

University Hospital of North Norway
University of Tromso
The Royal Norwegian Ministry of Health
Odd Berg Medical research Foundation

Investigators

Principal Investigator: Terje K. Steigen, MD, PhD, Dept. of Cardiology, University Hospital of North Norway and University of Tromsø, Norway
Study Chair: Ingrid Toft, MD, PhD, Dept. of Nephrology, University Hospital of North Norway and University of Tromsø
Study Director: Marit D Solbu, MD, PhD, Dept of Nephrology, University Hospital of North Norway and University of Tromsø