Renal Denervation in Chronic Kidney Disease - RDN-CKD Study

• Sponsor: University of Erlangen-Nürnberg Medical School (Other)
• Overall Status: Recruiting
• CT.gov ID: NCT04264403
• Collaborator: (none)
• Enrollment: 80
• Locations: 4
• Arms: 2
• Anticipated Duration (Months): 41
• Patients Per Site: 20
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Uncontrolled Hypertension; Renal Denervation; Chronic Kidney Disease stage3	Device: Renal denervation	N/A

Detailed Description

1. 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.

2. 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.

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.

4. 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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention 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.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 (Participant, Care Provider, Outcomes Assessor)
• Masking Description: 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, 6 months and 12 months FU.
• Primary Purpose: Treatment
• Official Title: Effect of Renal Denervation on Blood Pressure in Patients With Chronic Kidney Disease and Uncontrolled Hypertension
• Actual Study Start Date: Jan 23, 2020
• Anticipated Primary Completion Date: Mar 23, 2023
• Anticipated Study Completion Date: Jun 23, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Renal Denervation 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; 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.
No Intervention: Sham Procedere 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.

Outcome Measures

Primary Outcome Measures

1. change in systolic 24-h ambulatory BP [at 6 month post-procedure]

   compared between the 2 groups

Secondary Outcome Measures

1. Change in systolic 24-h ambulatory BP [at 3 and 12 month post-procedure]

   compared between the 2 groups.

2. Change in diastolic 24-h ambulatory BP at 3, 6 and 12 months post-procedure [at 3, 6 and 12 months post-procedure]

   compared between the 2 groups

3. Change in office (attended) systolic and diastolic BP [at 3, 6 and 12 months post-procedure]

   between the 2 groups

4. Responder rate in BP (systolic office (attended) BP ≥10 mmHg, 24-h systolic ambulatory BP ≥ 5 mmHg) [at 3, 6 and 12 months post-procedure]

   compared between the 2 groups

5. Change in estimated glomerular filtration rate [eGFR] [at 3, 6 and 12 months post-procedure]

   compared between the 2 groups

6. Change of the slope of eGFR [after half year and one year post-procedure]

   compared between the 2 groups

7. Change of the slope of eGFR [at 1 year post-procedure]

   compared to the historical slope the year before

8. Change in albuminuria quantitatively and by category [at 6 and 12 months post-procedure]

   compared between the 2 groups

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Heinrich Heine University Düsseldorf, Nephrologie, Germany	Duesseldorf		Germany	40225
2	Clinical Research Center, Department of Nephrology and Hypertension, University of Erlangen-Nuremberg	Erlangen		Germany	91054
3	Klinik für Innere Medizin III, Kardiologie, Angiologie Und Internistische Intensivmedizin, Saarland University Hospital, Saarland University	Homburg		Germany	66421
4	Clinical Research Center Nuremberg, Department of Nephrology, University Hospital Erlangen	Nuremberg		Germany

Sponsors and Collaborators

• University of Erlangen-Nürnberg Medical School

Investigators

• Principal Investigator: Roland E Schmieder, MD, Clinical Research Center, Department of Nephrology and Hypertension, University of Erlangen-Nuremberg

Study Documents (Full-Text)

None provided.

More Information

Publications

• Azizi M, Sapoval M, Gosse P, Monge M, Bobrie G, Delsart P, Midulla M, Mounier-Véhier C, Courand PY, Lantelme P, Denolle T, Dourmap-Collas C, Trillaud H, Pereira H, Plouin PF, Chatellier G; Renal Denervation for Hypertension (DENERHTN) investigators. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial. Lancet. 2015 May 16;385(9981):1957-65. doi: 10.1016/S0140-6736(14)61942-5. Epub 2015 Jan 26.
• Azizi M, Schmieder RE, Mahfoud F, Weber MA, Daemen J, Davies J, Basile J, Kirtane AJ, Wang Y, Lobo MD, Saxena M, Feyz L, Rader F, Lurz P, Sayer J, Sapoval M, Levy T, Sanghvi K, Abraham J, Sharp ASP, Fisher NDL, Bloch MJ, Reeve-Stoffer H, Coleman L, Mullin C, Mauri L; RADIANCE-HTN Investigators. Endovascular ultrasound renal denervation to treat hypertension (RADIANCE-HTN SOLO): a multicentre, international, single-blind, randomised, sham-controlled trial. Lancet. 2018 Jun 9;391(10137):2335-2345. doi: 10.1016/S0140-6736(18)31082-1. Epub 2018 May 23. Erratum in: Lancet. 2018 Sep 8;392(10150):820.
• Chowdhury EK, Langham RG, Ademi Z, Owen A, Krum H, Wing LM, Nelson MR, Reid CM; Second Australian National Blood Pressure Study Management Committee. Rate of change in renal function and mortality in elderly treated hypertensive patients. Clin J Am Soc Nephrol. 2015 Jul 7;10(7):1154-61. doi: 10.2215/CJN.07370714. Epub 2015 Apr 21.
• Converse RL Jr, Jacobsen TN, Toto RD, Jost CM, Cosentino F, Fouad-Tarazi F, Victor RG. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med. 1992 Dec 31;327(27):1912-8.
• Hering D, Mahfoud F, Walton AS, Krum H, Lambert GW, Lambert EA, Sobotka PA, Böhm M, Cremers B, Esler MD, Schlaich MP. Renal denervation in moderate to severe CKD. J Am Soc Nephrol. 2012 Jul;23(7):1250-7. doi: 10.1681/ASN.2011111062. Epub 2012 May 17.
• Kandzari DE, Böhm M, Mahfoud F, Townsend RR, Weber MA, Pocock S, Tsioufis K, Tousoulis D, Choi JW, East C, Brar S, Cohen SA, Fahy M, Pilcher G, Kario K; SPYRAL HTN-ON MED Trial Investigators. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet. 2018 Jun 9;391(10137):2346-2355. doi: 10.1016/S0140-6736(18)30951-6. Epub 2018 May 23.
• Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, Ford CE, Shulman NB, Stamler J. Blood pressure and end-stage renal disease in men. N Engl J Med. 1996 Jan 4;334(1):13-8.
• Krum H, Schlaich MP, Sobotka PA, Böhm M, Mahfoud F, Rocha-Singh K, Katholi R, Esler MD. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet. 2014 Feb 15;383(9917):622-9. doi: 10.1016/S0140-6736(13)62192-3. Epub 2013 Nov 7. Erratum in: Lancet. 2014 Feb 15;383(9917):602. Sobotka, Paul A [added].
• Mahfoud F, Cremers B, Janker J, Link B, Vonend O, Ukena C, Linz D, Schmieder R, Rump LC, Kindermann I, Sobotka PA, Krum H, Scheller B, Schlaich M, Laufs U, Böhm M. Renal hemodynamics and renal function after catheter-based renal sympathetic denervation in patients with resistant hypertension. Hypertension. 2012 Aug;60(2):419-24. doi: 10.1161/HYPERTENSIONAHA.112.193870. Epub 2012 Jun 25.
• Mahfoud F, Schmieder RE, Azizi M, Pathak A, Sievert H, Tsioufis C, Zeller T, Bertog S, Blankestijn PJ, Böhm M, Burnier M, Chatellier G, Durand Zaleski I, Ewen S, Grassi G, Joner M, Kjeldsen SE, Lobo MD, Lotan C, Lüscher TF, Parati G, Rossignol P, Ruilope L, Sharif F, van Leeuwen E, Volpe M, Windecker S, Witkowski A, Wijns W. Proceedings from the 2nd European Clinical Consensus Conference for device-based therapies for hypertension: state of the art and considerations for the future. Eur Heart J. 2017 Nov 21;38(44):3272-3281. doi: 10.1093/eurheartj/ehx215. Review. Erratum in: Eur Heart J. 2018 May 1;39(17):1534.
• Oparil S, Schmieder RE. New approaches in the treatment of hypertension. Circ Res. 2015 Mar 13;116(6):1074-95. doi: 10.1161/CIRCRESAHA.116.303603. Review.
• Ott C, Mahfoud F, Schmid A, Toennes SW, Ewen S, Ditting T, Veelken R, Ukena C, Uder M, Böhm M, Schmieder RE. Renal denervation preserves renal function in patients with chronic kidney disease and resistant hypertension. J Hypertens. 2015 Jun;33(6):1261-6. doi: 10.1097/HJH.0000000000000556.
• Ott C, Schmid A, Ditting T, Veelken R, Uder M, Schmieder RE. Effects of renal denervation on blood pressure in hypertensive patients with end-stage renal disease: a single centre experience. Clin Exp Nephrol. 2019 Jun;23(6):749-755. doi: 10.1007/s10157-019-01697-7. Epub 2019 Feb 19.
• Schlaich MP, Bart B, Hering D, Walton A, Marusic P, Mahfoud F, Böhm M, Lambert EA, Krum H, Sobotka PA, Schmieder RE, Ika-Sari C, Eikelis N, Straznicky N, Lambert GW, Esler MD. Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease. Int J Cardiol. 2013 Oct 3;168(3):2214-20. doi: 10.1016/j.ijcard.2013.01.218. Epub 2013 Feb 28.
• Townsend RR, Mahfoud F, Kandzari DE, Kario K, Pocock S, Weber MA, Ewen S, Tsioufis K, Tousoulis D, Sharp ASP, Watkinson AF, Schmieder RE, Schmid A, Choi JW, East C, Walton A, Hopper I, Cohen DL, Wilensky R, Lee DP, Ma A, Devireddy CM, Lea JP, Lurz PC, Fengler K, Davies J, Chapman N, Cohen SA, DeBruin V, Fahy M, Jones DE, Rothman M, Böhm M; SPYRAL HTN-OFF MED trial investigators*. Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled, proof-of-concept trial. Lancet. 2017 Nov 11;390(10108):2160-2170. doi: 10.1016/S0140-6736(17)32281-X. Epub 2017 Aug 28.
• Veelken R, Schmieder RE. Renal denervation--implications for chronic kidney disease. Nat Rev Nephrol. 2014 Jun;10(6):305-13. doi: 10.1038/nrneph.2014.59. Epub 2014 Apr 15. Review.
• Vonend O, Marsalek P, Russ H, Wulkow R, Oberhauser V, Rump LC. Moxonidine treatment of hypertensive patients with advanced renal failure. J Hypertens. 2003 Sep;21(9):1709-17.

• Responsible Party: University of Erlangen-Nürnberg Medical School
• ClinicalTrials.gov Identifier: NCT04264403
• Other Study ID Numbers: RDN2019CKD
• First Posted: Feb 11, 2020
• Last Update Posted: Jan 21, 2022
• Last Verified: Jan 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of Erlangen-Nürnberg Medical School: Chronic Kidney Disease; Renal Denervation; Uncontrolled Hypertension
• Additional relevant MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic; Hypertension

Study Results

No Results Posted as of Jan 21, 2022