Renal Denervation in Chronic Kidney Disease - RDN-CKD Study

Study Overview
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Brief Summary
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RDN-CKD Study is a prospective, randomized (1:1, central randomization), double-blind (unblinded interventionalist and blinded study team at each center), sham controlled, multicenter feasibility study. The purpose of the RDN-CKD Study is to demonstrate that renal denervation (RDN) effectively reduces 24-h ambulatory BP in 80 patients with chronic kidney disease (CKD) stage 3a or 3b.

Detailed Description
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Introduction Uncontrolled hypertension is more prevalent in patients with chronic kidney disease (CKD) and the risk of developing end-stage renal disease is increased in patients with uncontrolled hypertension. Clinical and experimental studies have clearly shown that sympathetic nerve activity is increased in CKD and substantially aggravates the progression of CKD. Recent clinical studies have indicated that invasive, catheter-based renal denervation (RDN) decreases the sympathetic nerve activity in the whole body and in particular in the kidneys. In patients with primary hypertension washed off of antihypertensive medications, RDN has been found to significantly decrease blood pressure (BP) in two randomized, double blind, sham-controlled studies. Study Purpose The purpose of the RDN-CKD Study is to demonstrate that RDN effectively reduces 24-h ambulatory BP in patients with CKD stage 3. Study Design RDN-CKD Study is a prospective, randomized (1:1, central randomization), double-blind (unblinded interventionalist and blinded study team at each center), sham controlled, multicenter feasibility study. All centers have participated at least in one of the sham-controlled trials in primary hypertension thereby having established an unblinded and a blinded team. Patient Population 80 patients with CKD stages 3a or 3b (according to the currently used estimation formulas [MDRD, CKD-EPI] and uncontrolled hypertension. 5 Endpoints Primary Efficacy Endpoint The primary efficacy endpoint will be the change in systolic 24-h ambulatory BP at 6 months post-procedure compared between the 2 groups. 6 Visit and Follow-Up Schedule The primary efficacy endpoint will be assessed at 26 weeks (6 months) post-procedure in both cohorts; however, all subjects will be followed for a minimum of 12 months post-procedure. Scheduled in-clinic follow-up (FU) visits will occur at 3, 6, 12 (3 months), 19, 26 (6 months), 39 and 52 (12 months) weeks post procedure. 7 Blinding The subjects and all study personnel taking BP measurements will be blinded to the randomization. Subjects will complete a blinding assessment prior to hospital pre-discharge and at 3 weeks and 6 months FU. 8 Crossover to treatment Crossover of patients allocated to the sham group is allowed after 12 months. At that time, after 12 months of blinded FU, unblinding of the individual patient takes place. To be eligible for crossover treatment, patients have to fulfill the same BP criteria as specified at the inclusion criteria and exclusion criteria within the next 4 weeks after FU. All randomized patients will be included in a registry after 12 months to capture long-term safety signals. 9 Medication Adherence Adherence to drug therapy will be captured by interviewing patients, checking the patient's BP diary and by urinary toxicological analysis at baseline, 6 months, and 12 months visit. 10 Safety Signals A major combined safety endpoint is the incidence of any major adverse events (MAE) through the 12 months FU. 11 Study Geographies The RDN-CKD Study will be conducted at 4 clinical investigational sites, which are the University Hospitals in Erlangen, Homburg/Saar, Düsseldorf, and Nürnberg. 12 Escape Criteria Enrolled subjects will be excluded if office (attended) BP exceeds ≥170/105 mmHg confirmed by 7-day average of home blood pressure measurements ≥ BP >160/100 mmHg or confirmed by office (attended) BP ≥170/105 mmHg at another study visit. 13 Ethics The study will be conducted in accordance with the declaration of Helsinki, ISO 14155:2011, FDA 21 CFR parts 50, 54, 56, 812 and other applicable local and national regulations.

Official Title
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Effect of Renal Denervation on Blood Pressure in Patients With Chronic Kidney Disease and Uncontrolled Hypertension

Conditions
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Uncontrolled Hypertension, Renal Denervation, Chronic Kidney Disease stage3

Intervention / Treatment
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* Device: Renal denervation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: CKD stage 3 (eGFR 30-59 ml/min/1.73m² [according to the currently used estimation formulas: MDRD, CKD-EPI]) with diabetic or non-diabetic nephropathy Uncontrolled hypertension with 1-5 drug classes (renin angiotensin system [RAS] blockade is mandatory, unless intolerance to RAS blockers has been documented) and systolic office (attended) BP ≥140 mmHg confirmed by 24-h ambulatory BP systolic ≥130 mmHg Patient is adhering to a stable drug regimen including RAS blockade without changes for a minimum of 4 weeks. Individual is ≥ 18 years of age, both genders are included. Exclusion Criteria: Anatomically significant renal artery abnormality in either renal artery which in the eyes of the interventionalist would interfere with safe catheter Placement Other cause of Hypertension that can be treated by Intervention/surgery (e.g. hemodynamically relevant renal artery stenosis, functional adrenal adenoma) Prior renal denervation procedure Office (attended) BP ≥ 180 mmHg systolic and/or ≥ 110 mmHg diastolic 24-h ambulatory BP ≥ 160 mmHg systolic Anatomic or functional solitary kidney, kidney transplantation Lack of capturing serum creatinine levels in the past Secondary hypertension other than obstructive sleep apnea Type 1 diabetes mellitus Nephrotic syndrome Contraindication to magnetic resonance imaging (MRI) Individual has experienced a myocardial infarction, unstable angina pectoris, or a cerebrovascular accident within 3 months of the screening visit Acute episode of renal disease requiring uptitration of any immunosuppressive drug regimen within the last 3 months Subject is pregnant, nursing, or intends to become pregnant Enrollment in another interventional research protocol. Any condition that, at the discretion of the investigator, would preclude participation in the study (e.g. non-adherence)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: RDN-CKD Study is a prospective, randomized (1:1, central randomization), double-blind (unblinded interventionalist and blinded study team at each center), sham controlled, multicenter feasibility study.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Renal Denervation<br>All subjects will undergo a diagnostic, renal angiogram (based on clinical grounds to rule out renal artery stenosis) which should be per Institutional practice via femoral artery access. Randomization will occur following the diagnostic renal angiogram. If randomized to the Renal Denervation Group RDN procedure will be applied using the Paradise® Renal Denervation System. The Paradise® Renal Denervation System is a catheter-based device designed to use ultrasound energy to thermally ablate the afferent and efferent nerves surrounding the renal artery and serving the kidney. | Device: Renal denervation<br>* The Paradise® Renal Denervation System (Paradise System) is CE-marked in countries accepting the CE mark. The system is a catheter-based device designed to use ultrasound energy to thermally ablate the afferent and efferent nerves surrounding the renal artery and serving the kidney.<br>|
| No Intervention: Sham Procedere<br>All subjects will undergo a diagnostic, renal angiogram (based on clinical grounds to rule out renal artery stenosis) which should be per Institutional practice via femoral artery access. Randomization will occur following the diagnostic renal angiogram. In these patients no RDN will be performed. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in systolic 24-h ambulatory BP | compared between the 2 groups (updated; please see details in the SAP uploaded) | at 6 month post-procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in systolic 24-h ambulatory BP | compared between the 2 groups (updated; please see details in the SAP uploaded) | at 3 and 12 month post-procedure | 
| Change in diastolic 24-h ambulatory BP at 3, 6 and 12 months post-procedure | compared between the 2 groups (updated; please see details in the SAP uploaded) | at 3, 6 and 12 months post-procedure | 
| Change in office (attended) systolic and diastolic BP | between the 2 groups (updated; please see details in the SAP uploaded) | at 3, 6 and 12 months post-procedure | 
| Responder rate in BP (systolic office (attended) BP ≥10 mmHg, 24-h systolic ambulatory BP ≥ 5 mmHg) | compared between the 2 groups (updated; please see details in the SAP uploaded) | at 3, 6 and 12 months post-procedure | 
| Change in estimated glomerular filtration rate [eGFR] | compared between the 2 groups (updated; please see details in the SAP uploaded) | at 3, 6 and 12 months post-procedure | 
| Change of the slope of eGFR | compared between the 2 groups (updated; please see details in the SAP uploaded) | after half year and one year post-procedure | 
| Change of the slope of eGFR | compared to the historical slope the year before (updated; please see details in the SAP uploaded) | at 1 year post-procedure | 
| Change in albuminuria quantitatively and by category | compared between the 2 groups (updated; please see details in the SAP uploaded) | at 6 and 12 months post-procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Kidney Disease, Renal Denervation, Uncontrolled Hypertension