SPYRAL PIVOTAL - SPYRAL HTN-OFF MED Study

Global Clinical Study of Renal Denervation With the Symplicity Spyral™ Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications (SPYRAL PIVOTAL - SPYRAL HTN-OFF MED)

The purpose of this study is to test the hypothesis that renal denervation decreases blood pressure and is safe when studied in the absence of antihypertensive medications.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Diseases; Vascular Diseases; Hypertension
• Intervention / Treatment: Device: Symplicity Spyral™ multi-electrode renal denervation system; Procedure: Sham Procedure

• Study Type: Interventional
• Enrollment (Actual): 366
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Alfred Hospital
• Austria
  • Wels, Austria, 4600
    • Klinikum Wels-Grieskirchen
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5B 1W8
      • St. Michael's Hospital
  • Quebec
    • Montréal, Quebec, Canada, H1T 1C8
      • Institut de cardiologie de Montréal / Montreal Heart Institute
• Germany
  • Bad Krozingen, Germany, 79189
    • Universitäts-Herzzentrum Freiburg - Bad Krozingen GmbH
  • Erlangen, Germany, 91054
    • Universitatsklinikum Erlangen
  • Homburg, Germany, 66421
    • Universitätsklinikum des Saarlandes
  • Leipzig, Germany, 04289
    • Herzzentrum Leipzig, Universitätsklinik
  • Lübeck, Germany, 23560
    • Sana Kliniken Lübeck
• Greece
  • Athens, Greece, 11527
    • Hippokration General Hospital of Athens
  • Thessaloniki, Greece, 54621
    • University General Hospital of Thessaloniki (AHEPA)
• Ireland
  • Galway, Ireland
    • Galway University Hospital
• Japan
  • Tochigi
    • Shimotsuke, Tochigi, Japan, 329-0498
      • Jichi Medical University Hospital
  • Tokyo
    • Chiyoda, Tokyo, Japan, 101-8643
      • Mitsui Memorial Hospital
• United Kingdom
  • Cardiff, United Kingdom
    • Cardiff and Vale University Health Board - University Hospital of Wales
  • Exeter, United Kingdom, EX2 5DW
    • Royal Devon & Exeter NHS Foundation Trust
  • London, United Kingdom, W12 0HS
    • Imperial College Healthcare NHS Trust
• United States
  • Alabama
    • Huntsville, Alabama, United States, 35801
      • Heart Center Research, LLC
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Honor Health Research Institute
  • California
    • Los Angeles, California, United States, 90027
      • Kaiser Permanente LA Medical Center
    • Stanford, California, United States, 94305
      • Stanford Hospital and Clinics
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale New Haven Hospital
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Baptist Medical Center Jacksonville
    • Tallahassee, Florida, United States, 32308
      • Tallahassee Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30308
      • Emory University Hospital Midtown
    • Atlanta, Georgia, United States, 30309
      • Piedmont Heart Institute
  • Iowa
    • West Des Moines, Iowa, United States, 50266
      • Iowa Heart Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
  • Michigan
    • Pontiac, Michigan, United States, 48341
      • St Joseph Mercy Oakland
    • Southfield, Michigan, United States, 48075
      • Providence Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Minneapolis Heart Institute Foundation
  • Mississippi
    • Hattiesburg, Mississippi, United States, 39401
      • Hattiesburg Clinic
    • Tupelo, Mississippi, United States, 38801
      • Cardiology Associates Research LLC
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Barnes-jewish Hospital
  • New Jersey
    • Livingston, New Jersey, United States, 07039
      • Saint Barnabas Medical Center
  • New York
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
  • Pennsylvania
    • Harrisburg, Pennsylvania, United States, 17011
      • PinnacleHealth Cardiovascular Institute
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
  • Rhode Island
    • Providence, Rhode Island, United States, 02906
      • The Miriam Hospital
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • AnMed Health
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Centennial Medical Center
  • Texas
    • Dallas, Texas, United States, 75226
      • Baylor Heart & Vascular Hospital
  • West Virginia
    • Charleston, West Virginia, United States, 25304
      • Charleston Area Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora St. Luke's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Individual has office systolic blood pressure (SBP) ≥ 150 mmHg and <180 mmHg and a diastolic blood pressure (DBP) ≥ 90 mmHg after being off medications.
• Individual has 24-hour Ambulatory Blood Pressure Monitoring (ABPM) average SBP ≥ 140 mmHg and < 170 mmHg.
• Individual is willing to discontinue current antihypertensive medications.

Exclusion Criteria:

• Individual lacks appropriate renal artery anatomy.
• Individual has estimated glomerular filtration rate (eGFR) of <45.
• Individual has type 1 diabetes mellitus or poorly-controlled type 2 diabetes mellitus.
• Individual has one or more episodes of orthostatic hypotension.
• Individual requires chronic oxygen support or mechanical ventilation other than nocturnal respiratory support for sleep apnea.
• Individual has primary pulmonary hypertension.
• Individual is pregnant, nursing or planning to become pregnant.
• Individual has frequent intermittent or chronic pain that results in treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) for two or more days per week over the month prior to enrollment.
• Individual has stable or unstable angina within 3 months of enrollment, myocardial infarction within 3 months of enrollment; heart failure, cerebrovascular accident or transient ischemic attack, or atrial fibrillation at any time.
• Individual works night shifts.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Renal Denervation; Renal angiography and Renal Denervation (Symplicity Spyral™ multi-electrode renal denervation system)	Device: Symplicity Spyral™ multi-electrode renal denervation system; After a renal angiography according to standard procedures, subjects remain blinded and are immediately treated with the renal denervation procedure after randomization.; Other Names: Renal angiography; Renal Denervation
Sham Comparator: Sham Procedure; Renal angiography	Procedure: Sham Procedure; After a renal angiography according to standard procedures, subjects remain blinded and remain on the catheterization lab table for at least 20 minutes prior to introducer sheath removal.; Other Names: Renal angiography

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Major Adverse Events (MAE) Defined as a Composite of Events.	All-cause mortality End-stage Renal Disease (ESRD) Significant embolic event resulting in end-organ damage Renal artery perforation requiring intervention Renal artery dissection requiring intervention Vascular complications Hospitalization for hypertensive crisis not related to confirmed non-adherence with medications or the protocol New renal artery stenosis >70% (6 months for new renal artery stenosis, however endpoint data is reported to 3 months only)	From baseline to 1 month post-procedure
Baseline Adjusted Change (Using Analysis of Covariance) in Systolic Blood Pressure as Measured by 24-hour Ambulatory Blood Pressure Monitoring	The outcome measure is the change in ambulatory systolic blood pressure from baseline to 3-month. The unadjusted treatment difference between renal denervation and sham control groups is -3.9 mmHg. The baseline adjusted treatment difference is -3.9 mmHg.	From baseline to 3 months post-procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline Adjusted Change (Using Analysis of Covariance) in Office Systolic Blood Pressure	The outcome measure is the change in office systolic blood pressure from baseline to 3-month. The unadjusted treatment difference between renal denervation and sham control groups is -7.0 mmHg. The baseline adjusted treatment difference is -6.9 mmHg.	From baseline to 3 months post-procedure
Number of Participants With Significant Embolic Event Resulting in End-organ Damage	Significant embolic event resulting in end-organ damage (e.g. kidney/bowel infarct, lower extremity ulceration or gangrene, or doubling of serum creatinine documented by at least two measurements at least 21 days apart)	From baseline to 1 month post-procedure
Number of Participants With Renal Artery Perforation Requiring Intervention	Renal artery perforation requiring intervention	From baseline to 1 month post-procedure
Renal Artery Dissection	Number of Participants with Renal artery dissection requiring intervention	From baseline to 1 month post-procedure
Number of Participants With Vascular Complications	Vascular complications (e.g., clinically significant groin hematoma, arteriovenous fistula, pseudoaneurysm, excessive bleeding) requiring surgical repair, interventional procedure, thrombin injection, or blood transfusion (requiring more than 2 units of packed red blood cells within any 24 hour period during the first 7 days post renal denervation procedure).	From baseline to 1 month post-procedure
Number of Participants With End-stage Renal Disease	defined as two or more eGFR measurements < 15 mL/min/1.73m2 at least 21 days apart and requiring dialysis for one of more of the following: Volume management refractory to diuretics; Hyperkalemia unmanageable by diet and diuretics; Acidosis bicarbonate <18 unmanageable with HCO3 supplements; Symptoms of uremia, nausea, vomiting	From baseline to 1 month post-procedure
Number of Participants With Decline in eGFR	≥40% decline in eGFR	From baseline to 1 month post-procedure
Myocardial Infarction	Number of Participants with New myocardial infarction	From baseline to 1 month post-procedure
New Stroke	Number of Participants with New stroke	From baseline to 1 month post-procedure
Number of Participants With Renal Artery Re-intervention	Renal artery re-intervention	From baseline to 1 month post-procedure
Number of Participants With Major Bleeding According to TIMI Definition	Major bleeding according to TIMI definition (i.e. intracranial hemorrhage, ≥5g/dl decrease in hemoglobin concentration, a ≥15% absolute decrease in hematocrit, or death due to bleeding within 7 days of the procedure).	From baseline to 1 month post-procedure
Number of Participants With Increase in Serum Creatinine	Increase in serum creatinine > 50% from screening visit 2.	From baseline to 1 month post-procedure
Number of Participants With New Renal Artery Stenosis > 70%	Confirmed by angiography and as determined by the angiographic core laboratory.	From baseline to 6 month post-procedure
Number of Participants With Hospitalization for Hypertensive Crisis With Medications or the Protocol	Hospitalization for hypertensive crisis not related to confirmed non-adherence with medications or the protocol.	From baseline to 1 month post-procedure
Number of Participants With All-cause Mortality	All-cause mortality	From baseline to 3 months post-procedure
Number of Participants With Change in Systolic Blood Pressure as Measured by 24-hour ABPM		From baseline to 36 month post-procedure
Number of Participants With Incidence of Achieving Target Office Systolic Blood Pressure (SBP <140 mmHg)		From 1 month to 36 months post-procedure
Number of Participants With Change in Office Diastolic Blood Pressure	Change in office diastolic blood pressure	From baseline to 36 months post-procedure
Number of Participants With Change in Diastolic Blood Pressure as Measured by 24-hour ABPM	Change in diastolic blood pressure as measured by 24-hour ABPM	From baseline to 36 months post-procedure
Number of Participants With End-Stage Renal Disease (ESRD)	Defined as two or more eGFR measurements < 15 mL/min/1.73m2 at least 21 days apart and requiring dialysis for one of more of the following: Volume management refractory to diuretics; Hyperkalemia unmanageable by diet and diuretics; Acidosis bicarbonate <18 unmanageable with HCO3 supplements; Symptoms of uremia, nausea, vomiting	From baseline to 3 months post randomization
Number of Participants With ≥40% Decline in eGFR	≥40% Decline in eGFR	From baseline to 3 months post randomization
Number of Participants With New Myocardial Infarction	New Myocardial Infarction	From baseline to 3 months post randomization
New Stroke	Number of Participants with New Stroke	From baseline to 3 months post randomization
Number of Participants With Renal Artery Re-intervention	Renal Artery Re-intervention	From baseline to 3 months post randomization
Number of Participants With Major Bleeding According to TIMI Definition	Major bleeding according to TIMI definition (i.e. intracranial hemorrhage, ≥5g/dl decrease in hemoglobin concentration, a ≥15% absolute decrease in hematocrit, or death due to bleeding within 7 days of the procedure).	From baseline to 3 months post randomization
Increase in Serum Creatinine	Number of Participants with Increase in Serum Creatinine > 50% from screening visit 2.	From baseline to 3 months post randomization
Number of Participants With Hospitalization for Hypertensive Crisis	Hospitalization for Hypertensive Crisis Not Related to Confirmed Nonadherence With Medications or the Protocol	From baseline to 3 months post randomization
Change in Office Systolic Blood Pressure	Change in office systolic blood pressure from baseline (Screening Visit 2) to 1-month	From baseline to 1 month post procedure
Number of Participants Achieving Target Office Systolic Blood Pressure	Incidence of achieving target office systolic blood pressure (SBP <140 mmHg)	From baseline to 1 month post procedure
Number of Participants Achieving Target Office Systolic Blood Pressure	Incidence of Achieving Target Office Systolic Blood Pressure (SBP <140 mmHg)	From baseline to 3 months post procedure
Change in Office Diastolic Blood Pressure	Change in office diastolic blood pressure from baseline (Screening Visit 2)	From baseline to 1 month post procedure
Change in Office Diastolic Blood Pressure	Change in Office Diastolic Blood Pressure From Baseline (Screening Visit 2) to 3-months	From baseline to 3 months post procedure
Change in Diastolic Blood Pressure as Measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM)	Change in diastolic blood pressure from baseline (screening visit 2) to 3-month as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM).	From baseline to 3 months post procedure

Collaborators and Investigators

• Sponsor: Medtronic Vascular
• Investigators: Principal Investigator: Raymond Townsend, MD, University of Pennsylvania; Principal Investigator: David Kandzari, MD, Piedmont Hospital; Principal Investigator: Michael Böhm, MD, Universitätskliniken des Saarlandes; Principal Investigator: Kazuomi Kario, MD, Jichi Medical University

Publications and helpful links

General Publications

• Bohm M, Townsend RR, Kario K, Kandzari D, Mahfoud F, Weber MA, Schmieder RE, Tsioufis K, Hickey GL, Fahy M, DeBruin V, Brar S, Pocock S. Rationale and design of two randomized sham-controlled trials of catheter-based renal denervation in subjects with uncontrolled hypertension in the absence (SPYRAL HTN-OFF MED Pivotal) and presence (SPYRAL HTN-ON MED Expansion) of antihypertensive medications: a novel approach using Bayesian design. Clin Res Cardiol. 2020 Mar;109(3):289-302. doi: 10.1007/s00392-020-01595-z. Epub 2020 Feb 7. Erratum In: Clin Res Cardiol. 2020 May;109(5):653.
• Kandzari DE, Kario K, Mahfoud F, Cohen SA, Pilcher G, Pocock S, Townsend R, Weber MA, Bohm M. The SPYRAL HTN Global Clinical Trial Program: Rationale and design for studies of renal denervation in the absence (SPYRAL HTN OFF-MED) and presence (SPYRAL HTN ON-MED) of antihypertensive medications. Am Heart J. 2016 Jan;171(1):82-91. doi: 10.1016/j.ahj.2015.08.021. Epub 2015 Sep 11.
• Weber MA, Schmieder RE, Kandzari DE, Townsend RR, Mahfoud F, Tsioufis K, Kario K, Pocock S, Tatakis F, Ewen S, Choi JW, East C, Lee DP, Ma A, Cohen DL, Wilensky R, Devireddy CM, Lea JP, Schmid A, Fahy M, Bohm M. Hypertension urgencies in the SPYRAL HTN-OFF MED Pivotal trial. Clin Res Cardiol. 2022 Nov;111(11):1269-1275. doi: 10.1007/s00392-022-02064-5. Epub 2022 Jul 19.
• Bohm M, Tsioufis K, Kandzari DE, Kario K, Weber MA, Schmieder RE, Townsend RR, Kulenthiran S, Ukena C, Pocock S, Ewen S, Weil J, Fahy M, Mahfoud F. Effect of Heart Rate on the Outcome of Renal Denervation in Patients With Uncontrolled Hypertension. J Am Coll Cardiol. 2021 Sep 7;78(10):1028-1038. doi: 10.1016/j.jacc.2021.06.044.
• Mahfoud F, Townsend RR, Kandzari DE, Kario K, Schmieder RE, Tsioufis K, Pocock S, David S, Patel K, Rao A, Walton A, Bloom JE, Weber T, Suppan M, Lauder L, Cohen SA, McKenna P, Fahy M, Bohm M, Weber MA. Changes in Plasma Renin Activity After Renal Artery Sympathetic Denervation. J Am Coll Cardiol. 2021 Jun 15;77(23):2909-2919. doi: 10.1016/j.jacc.2021.04.044. Epub 2021 May 3.
• Bohm M, Kario K, Kandzari DE, Mahfoud F, Weber MA, Schmieder RE, Tsioufis K, Pocock S, Konstantinidis D, Choi JW, East C, Lee DP, Ma A, Ewen S, Cohen DL, Wilensky R, Devireddy CM, Lea J, Schmid A, Weil J, Agdirlioglu T, Reedus D, Jefferson BK, Reyes D, D'Souza R, Sharp ASP, Sharif F, Fahy M, DeBruin V, Cohen SA, Brar S, Townsend RR; SPYRAL HTN-OFF MED Pivotal Investigators. Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial. Lancet. 2020 May 2;395(10234):1444-1451. doi: 10.1016/S0140-6736(20)30554-7. Epub 2020 Mar 29.
• 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, Bohm 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2015
• Primary Completion (Actual): April 30, 2020
• Study Completion (Actual): October 25, 2023

Study Registration Dates

• First Submitted: April 28, 2015
• First Submitted That Met QC Criteria: May 6, 2015
• First Posted (Estimated): May 12, 2015

Study Record Updates

• Last Update Posted (Actual): April 18, 2024
• Last Update Submitted That Met QC Criteria: April 16, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Uncontrolled hypertension; Renal denervation
• Additional Relevant MeSH Terms: Hypertension; Cardiovascular Diseases; Vascular Diseases
• Other Study ID Numbers: SPYRAL HTN-OFF MED

Drug and device information, study documents

• Studies a U.S. FDA-regulated device product: Yes