Renal Denervation in ADPKD- RDN-ADPKD Study

Study Overview
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Brief Summary
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RDN-ADPKD is a prospective, randomized (1:1, central randomization), single-center, hypothesis-generating, feasibility study. The purpose of the RDN-ADPKD study is to demonstrate efficacy and document safety of renal denervation (RDN) with the Paradise System in hypertensive patients with ADPKD.

Detailed Description
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Introduction:Increased blood pressure (BP) is a common finding in patients with autosomal dominant polycystic kidney disease (ADPKD) which is one of the leading causes of end stage renal disease. Previously, it was shown that hypertensive patients with ADPKD have increased sympathetic nerve activity regardless of renal function. This was one of the pathogenetic mechanisms that leads to the progression of renal failure, even independent of BP. Recent clinical studies have indicated that invasive, catheter-based renal denervation (RDN) decreases sympathetic nerve activity. Up to date, only two single case reports have suggested a safe and effective procedure of RDN in an ADPKD patient with uncontrolled hypertension. Study purpose: The purpose of the RDN-ADPKD pilot study is to demonstrate efficacy and document safety of RDN with the Paradise System in hypertensive patients with ADPKD. Study design: RDN-ADPKD is a prospective, randomized (1:1, central randomization), single-center, hypothesis-generating, feasibility study. Patients are randomized into (immediate) I-RDN-group and (delayed) D-RDN-group, respectively. After 3 months, patients in the D-RDN-group will undergo RDN-procedure and will be followed for additional 36 months. Hence, study design allows several comparisons both of whole study group (at same time-point of follow-up) as well as between I-RDN-group and D-RDN-group. Patient population: 44 hypertensive patients with ADPKD are randomized with 22 patients allocated to the I-RDN-group and 22 patients to the D-RDN-group (receiving RDN after 3 months), respectively. Primary endpoint: The primary endpoint of this pilot study is the change in systolic 24-h ambulatory BP at 3 months post-procedure in the whole study group (irrespective whether treated immediate [I-RDN-group] or delayed [D-RDN-group]) compared to baseline. Visit and Follow-Up Schedule: The primary objective will be assessed at 13 weeks (3 months) post-procedure in both groups. Scheduled in-clinic follow-up (FU) visits will occur at least at 13 (3 months) and 26 (6 months) 52 (12 months), 78 weeks (18 months),104 weeks (24 months), 130 weeks (30 months) and 156 weeks (36 months) post procedure; however, scheduled Follow-Up visits at 3, 7,20 weeks, 78 weeks and 130 weeks post-procedure are possible as in-clinic FU visit as well as ambulant visit at the allocation centre(s) of the referring physician. Randomization: The subjects will be randomized to I-RDN group or D-RDN group at Visit 2. 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, 26 weeks, 52 weeks, 104 weeks and 156 weeks post-procedure visit. Safety Signals: A major combined safety endpoint is the incidence of any major adverse events (MAE) through the 36 months Follow-up. Escape Criteria: Enrolled subjects will be excluded: if home BP increases to ≥160 systolic or ≥100 mmHg diastolic pre-randomization, confirmed by office (attended) BP ≥170/105 mmHg will be excluded if office (attended) BP exceeds ≥170/105 mmHg pre-randomization, confirmed by 7-day average of home BP measurements ≥ 160/100 mmHg (excluding white coat effect) or confirmed by office (attended) BP ≥170/105 mmHg at another study visit. Ethics: The study will be conducted in accordance with the declaration of Helsinki, REGULATION (EU) 2017/745, EN ISO 14155:2020, 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 in Hypertensive Patients With Autosomal Dominant Polycystic Kidney Disease

Conditions
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Uncontrolled Hypertension, Autosomal Dominant Polycystic Kidney Disease, Renal Denervation

Intervention / Treatment
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* Device: Renal denervation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with ADPKD Systolic office (attended) BP ≥130 mmHg or diastolic office (attended) BP ≥80 mmHg confirmed by 24-h ambulatory BP systolic ≥125 mmHg or diastolic ≥75 mmHg despite treatment with 1-4 drug classes (RAS blockade is mandatory, unless intolerance to RAS blockers has been documented) The rationale of these inclusion criteria reflect the November 2021 updated knowledge of RDN according to international consensus reports, in particular in face of conducting clinic studies and randomized controlled trials and does not necessarily reflect the current application of RDN in clinical practice). Moreover, the most recent updated KDIGO guidelines recommend a target office BP < 120 mmHg in patients with chronic kidney disease.1. Patient is adhering to a stable drug regimen without changes for a minimum of 4 weeks Individual is ≥ 18 years of age, both genders are included Exclusion Criteria: eGFR < 40ml/min/1.73m² (according to the currently used estimation formulas: MDRD (Modification of Diet in Renal Disease), CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)) Anatomically significant renal artery abnormality in either renal artery which in the eyes of the interventionalist would interfere with safe catheter placement Prior renal denervation procedure Office (attended) BP ≥180 mmHg systolic and/or ≥110 mmHg diastolic 24-h ambulatory BP ≥160 mmHg systolic Other cause of hypertension that can be treated by intervention/surgery (e.g. hemodynamically relevant renal artery stenosis, functional adrenal adenoma) Type 1 diabetes mellitus Proteinuria (>3g/g Kreatinin) Contraindication to MRI Individual has experienced a myocardial infarction, unstable angina pectoris, or a cerebrovascular accident within 3 months of the screening visit 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

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: Parallel Assignment
Interventional Model Description: RDN-ADPKD is a prospective, randomized (1:1, central randomization), single-centre, hypothesis-generating, feasibility study. Patients are randomized into I-RDN-group and D-RDN-group, respectively. After 3 months, patients in the D-RDN-group will undergo RDN-procedure and will be followed for additional 36 months. Hence, study design allows several comparisons both of whole study group (at same time-point of follow-up) as well as between I-RDN-group and D-RDN-group.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Immediate Renal Denervation Group (I-RDN-group)<br>Patients are randomized into (immediate) I-RDN-group and (delayed) D-RDN-group, respectively. All subjects in the I-RDN-group will undergo a diagnostic, renal angiogram immediately (based on clinical grounds to rule out renal artery stenosis), which should be per Institutional practice via femoral artery access. Renal Denervation 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>|
| Other: Delayed Renal Denervation Group (D-RDN-group)<br>3 months after randomization, patients in the (delayed) D-RDN-group will undergo renal denervation procedure after undergoing a diagnostic, renal angiogram and will be followed for additional 36 months. | 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>|

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 [whole study group] | change in systolic 24-h ambulatory BP at 3 months post-procedure from pre-treatment in the whole study group (irrespective whether treated immediate [I-RDN-group] or delayed [D-RDN-group]). | 3 months post-procedure | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in diastolic 24-h ambulatory BP [whole study group] | Change in diastolic 24-h ambulatory BP at 3 months post-procedure in the whole study group (irrespetive whether treated immmediate (I-RDN-group) or delayed (D-RDN-group) compared to pre-treatment | 3 months post-procedure | 
| Change in systolic and diastolic 24-h ambulatory BP [whole study group] | Change in systolic and diastolic 24-h ambulatory BP at 6, 12, 18, 24, 30 and 36 months post-procedure in the whole study group (irrespective whether treated immediate [I-RDN-group] or delayed [D-RDN-group]) compared to pre-treatment | 6, 12, 18, 24, 30, 36 months post-procedure | 
| Change in systolic and diastolic 24-h ambulatory BP [separate study groups] | Change in systolic and diastolic 24-h ambulatory BP at 3 months post-procedure from pre-treatment in the I-RDN-group versus the change in systolic 24-h ambulatory BP prior procedure from pre-treatment in D-RDN-group | 3 months post-procedure | 
| Responder rate in BP [separate study groups] | Responder rate in BP (systolic office BP ≥ 5 mmHg, or 24-h systolic ambulatory BP ≥ 3 mmHg) at 3 months pre-treatment in the I-RDN-group versus responder rate in BP from pre-treatment to 3 months later in the D-RDN-group. | 3 months post-procedure | 
| Change in systolic and diastolic office (attended) BP [whole study group] | Change in systolic and diastolic office (attended) BP at 3, 6, 12, 18 and 24, 30, 36 months post-procedure in the whole study group compared to pre-treatment | 3, 6, 12, 18, 24, 30, 36 months post-procedure | 
| Change in systolic and diastolic office (attended) BP [separate study groups] | Change in systolic office (attended) BP at 3 months post-procedure from pre-treatment in the I-RDN-group versus the change prior procedure from pre-treatment in D-RDN-group | 3 months post-procedure | 
| Change in systolic and diastolic home BP (IEM-Tel-O-Graph-GSM) [whole study group] | Change in systolic and diastolic home BP (IEM-Tel-O-Graph-GSM) at 3, 6, 12, 24 and 36 months post-procedure in the whole study group compared to pre-treatment | 3, 6, 12, 24 and 36 months post-procedure | 
| Change in systolic and diastolic home BP (IEM-Tel-O-Graph-GSM) [separate study groups] | Change in systolic and diastolic home BP at 3 months post-procedure in the I-RDN-group versus the change prior procedure from pre-treatment in D-RDN-group. | 3 months post-procedure | 
| Win ratio analysis (BP change and decrease of medication number) [separate study groups] | Win ratio analysis will be conducted, with the criteria 24h ambulatory systolic BP change > 3 mmHg, office systolic BP change > 5 mmHg, and decrease of medication number from pre-treatment to 3 month post procedure in the I-RDN group versus pre-treatment to 3 months later in D-RDN-group. | 3 months post-procedure | 
| Win ratio analysis (BP change and decrease of drug burden index ) [separate study groups] | Win ratio analysis will be conducted, with the criteria 24h ambulatory systolic BP change > 3 mmHg, office systolic BP change > 5 mmHg, and any decrease of drug burden index from pre-treatment to 3 month post procedure in the I-RDN group versus pre-treatment to 3 months later in D-RDN-group. | 3 months post-procedure | 
| Win ratio analysis (BP change and decrease of antihypertensive load index ) [separate study groups] | Win ratio analysis will be conducted, with the criteria 24h ambulatory systolic BP change > 3 mmHg, office systolic BP change > 5 mmHg, and any decrease of antihypertensive load index from pre-treatment to 3 month post procedure in the I-RDN group versus pre-treatment to 3 months later in D-RDN-group | 3 months post-procedure | 
| Change in serum creatinine derived estimated glomerular filtration rate (eGFR) [whole study group] | Change in serum creatinine derived estimated glomerular filtration rate (eGFR) at 3, 6, 12, 18 and 24, 30 and 36 months post-procedure in the whole study group compared to pre-treatment | 3, 6, 12, 18 and 24, 30, 36 months post-procedure | 
| Change in cystatin C derived eGFR [whole study group] | Change in cystatin C derived estimated glomerular filtration rate (eGFR) at 3, 6, 12, 18 and 24, 30, 36 months post-procedure in the whole study group compared to pre-treatment | 3, 6, 12, 18 and 24, 30, 36 months post-procedure | 
| Change in total kidney volume (assessed by magnetic resonance imaging) [whole study group] | Change in total kidney volume (assessed by magnetic resonance imaging) at 6, 12, 24, 36 months post-procedure in the whole study group compared to pre-treatment | 6, 12, 24, 36 months post-procedure | 
| Change in measured GFR (assessed by single-shot iohexol clearance) [whole study group] | Change in measured GFR (assessed by single-shot iohexol clearance) at 6, 12, 24 and 36 months post-procedure in the whole study group compared to pre-treatment | 6, 12, 24, 36 months post-procedure | 
| Change in proteinuria [whole study group] | Change in proteinuria (per g urinary creatinine) at 3, 6, 12, 18, 24, 30 and 36 months post-procedure from pre-treatment. | 3, 6, 12, 18, 24, 30 and 36 months post-procedure | 
| Change in albuminuria [whole study group] | Change in albuminuria (per g urinary creatinine) at 3, 6, 12, 18, 24, 30 and 36 months post-procedure from pre-treatment. | 3, 6, 12, 18, 24, 30 and 36 months post-procedure | 
| Change in urine sodium [whole study group] | Change in urine sodium (per g urinary creatinine) at 3, 6, 12, 18, 24, 30 and 36 months post-procedure from pre-treatment. | 3, 6, 12, 18, 24, 30 and 36 months post-procedure | 
| Change in urine potassium [whole study group] | Change in urine potassium (per urinary creatinine) at 3, 6, 12, 18, 24, 30 and 36 months post-procedure from pre-treatment. | 3, 6, 12, 18, 24, 30 and 36 months post-procedure | 
| Change in urine creatinine concentration [whole study group] | Change in urine creatinine concentration at 3, 6, 12, 18, 24, 30 and 36 months post-procedure from pre-treatment. | 3, 6, 12, 18, 24, 30 and 36 months post-procedure | 
| Change of the slope of eGFR [whole study group] | Change of the slope of eGFR after 3, 6, 12, 18, 24, 30 and 36 months post-procedure from pre-treatment compared to the historical slope the year before in the total study group. | 3, 6, 12, 18, 24, 30 and 36 months post-procedure | 
| Change in serum creatinine derived eGFR [separate study groups] | Change in serum creatinine derived eGFR at 3 months post-procedure from pre-treatment in the I-RDN-group versus the change prior procedure from pre-treatment in D-RDN-group | 3 months post-procedure | 
| Change in cystatin C derived eGFR [separate study groups] | Change in cystatin C derived eGFR at 3, 6, 12, 18 and 24, 30, 36 months post-procedure from pre-treatment in the I-RDN-group versus the change prior procedure from pre-treatment in D-RDN-group | 3 months post-procedure | 
| Change in proteinuria [separate study groups] | Change in proteinuria from pre-procedure pre-treatment in the I-RDN-group versus the change from pre-treatment to 3 months later in the D-RDN-group. | 3 months post-procedure | 
| Change in albuminuria [separate study groups] | Change in albuminuria from pre-procedure pre-treatment in the I-RDN-group versus the change from pre-treatment to 3 months later in the D-RDN-group. | 3 months post-procedure | 
| Change in urine sodium [separate study groups] | Change in urine sodium from pre-procedure pre-treatment in the I-RDN-group versus the change from pre-treatment to 3 months later in the D-RDN-group. | 3 months post-procedure | 
| Change in urine potassium [separate study groups] | Change in urine potassium from pre-procedure pre-treatment in the I-RDN-group versus the change from pre-treatment to 3 months later in the D-RDN-group. | 3 months post-procedure | 
| Change in urine creatinine concentration [separate study groups] | Change in urine creatinine concentration from pre-procedure pre-treatment in the I-RDN-group versus the change from pre-treatment to 3 months later in the D-RDN-group. | 3 months post-procedure | 
| Change of the slope of eGFR [separate study groups] | Change of the slope of eGFR after 3 month post-procedure from pre-treatment (including eGFR values) in the I-RDN group compared to change after 3 month FU from pre-treatment in the D-RDN group. | 3 month post-procedure | 
| Level of pain (related to autosomal dominant polycystic kidney disease) determined by the use of a visual analogue scale [whole study group] | Level of pain (related to autosomal dominant polycystic kidney disease) determined by the use of a visual analogue scale (minimum value=0, representing no pain; maximum value=100, representing most imaginable pain) at 3, 6, 12, 24, 36 months post-procedure in the whole study group compared to pre-treatment. | 3, 6, 12, 24, 36 months post-procedure | 
| Change in Quality of life (QoL) (e.g. EQ-5D-5L) [whole study group] | Change in Quality of life (QoL) (e.g. EQ-5D-5L; minimum value=0, representing best imaginable health status; maximum value=100, representing worst imaginable health status) at 3, 6, 12, 24 and 36 months post-procedure in the whole study group compared to pre-treatment | 3, 6, 12, 24 and 36 months post-procedure | 
| Change in plasma and urinary biomarkers (e.g. albumin, copeptin) | Change in plasma and urinary biomarkers (e.g. albumin, copeptin) at 6, 12 months post-procedure in the whole study group compared to pre-treatment | 6, 12 months post-procedure | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal denervation, Uncontrolled Hypertension, Autosomal Dominant Polycystic Kidney Disease