SPYRAL PIVOTAL - SPYRAL HTN-OFF MED Study

• ClinicalTrials.gov Identifier: NCT02439749
• Recruitment Status: Active, not recruiting
• First Posted: May 12, 2015
• Results First Posted: May 27, 2021
• Last Update Posted: May 11, 2022
• Sponsor: Medtronic Vascular
• Information provided by (Responsible Party): Medtronic Vascular

Tracking Information

• First Submitted Date: April 28, 2015
• First Posted Date: May 12, 2015
• Results First Submitted Date: April 30, 2021
• Results First Posted Date: May 27, 2021
• Last Update Posted Date: May 11, 2022
• Actual Study Start Date: June 2015
• Actual Primary Completion Date: April 30, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 10, 2021)

• Number of Participants With Major Adverse Events (MAE) Defined as a Composite of Events. [ Time Frame: From baseline to 1 month post-procedure ]
  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)
• Baseline Adjusted Change (Using Analysis of Covariance) in Systolic Blood Pressure as Measured by 24-hour Ambulatory Blood Pressure Monitoring [ Time Frame: From baseline to 3 months post-procedure ]
  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.

Original Primary Outcome Measures (submitted: May 6, 2015)

• Acute and chronic safety by evaluating incidence of Major Adverse Events [ Time Frame: From baseline to 36 months post-procedure ]
• Change in systolic blood pressure as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM) [ Time Frame: From baseline to 36 months post-procedure ]

Current Secondary Outcome Measures (submitted: June 10, 2021)

• Baseline Adjusted Change (Using Analysis of Covariance) in Office Systolic Blood Pressure [ Time Frame: From baseline to 3 months post-procedure ]
  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.
• Number of Participants With Significant Embolic Event Resulting in End-organ Damage [ Time Frame: From baseline to 1 month post-procedure ]
  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)
• Number of Participants With Renal Artery Perforation Requiring Intervention [ Time Frame: From baseline to 1 month post-procedure ]
  Renal artery perforation requiring intervention
• Renal Artery Dissection [ Time Frame: From baseline to 1 month post-procedure ]
  Number of Participants with Renal artery dissection requiring intervention
• Number of Participants With Vascular Complications [ Time Frame: From baseline to 1 month post-procedure ]
  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).
• Number of Participants With End-stage Renal Disease [ Time Frame: From baseline to 1 month post-procedure ]
  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
• Number of Participants With Decline in eGFR [ Time Frame: From baseline to 1 month post-procedure ]
  ≥40% decline in eGFR
• Myocardial Infarction [ Time Frame: From baseline to 1 month post-procedure ]
  Number of Participants with New myocardial infarction
• New Stroke [ Time Frame: From baseline to 1 month post-procedure ]
  Number of Participants with New stroke
• Number of Participants With Renal Artery Re-intervention [ Time Frame: From baseline to 1 month post-procedure ]
  Renal artery re-intervention
• Number of Participants With Major Bleeding According to TIMI Definition [ Time Frame: From baseline to 1 month post-procedure ]
  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).
• Number of Participants With Increase in Serum Creatinine [ Time Frame: From baseline to 1 month post-procedure ]
  Increase in serum creatinine > 50% from screening visit 2.
• Number of Participants With New Renal Artery Stenosis > 70% [ Time Frame: From baseline to 6 month post-procedure ]
  Confirmed by angiography and as determined by the angiographic core laboratory.
• Number of Participants With Hospitalization for Hypertensive Crisis With Medications or the Protocol [ Time Frame: From baseline to 1 month post-procedure ]
  Hospitalization for hypertensive crisis not related to confirmed non-adherence with medications or the protocol.
• Number of Participants With All-cause Mortality [ Time Frame: From baseline to 3 months post-procedure ]
  All-cause mortality
• Number of Participants With Change in Systolic Blood Pressure as Measured by 24-hour ABPM [ Time Frame: From baseline to 36 month post-procedure ]
• Number of Participants With Incidence of Achieving Target Office Systolic Blood Pressure (SBP <140 mmHg) [ Time Frame: From 1 month to 36 months post-procedure ]
• Number of Participants With Change in Office Diastolic Blood Pressure [ Time Frame: From baseline to 36 months post-procedure ]
  Change in office diastolic blood pressure
• Number of Participants With Change in Diastolic Blood Pressure as Measured by 24-hour ABPM [ Time Frame: From baseline to 36 months post-procedure ]
  Change in diastolic blood pressure as measured by 24-hour ABPM
• Number of Participants With End-Stage Renal Disease (ESRD) [ Time Frame: From baseline to 3 months post randomization ]
  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
• Number of Participants With ≥40% Decline in eGFR [ Time Frame: From baseline to 3 months post randomization ]
  ≥40% Decline in eGFR
• Number of Participants With New Myocardial Infarction [ Time Frame: From baseline to 3 months post randomization ]
  New Myocardial Infarction
• New Stroke [ Time Frame: From baseline to 3 months post randomization ]
  Number of Participants with New Stroke
• Number of Participants With Renal Artery Re-intervention [ Time Frame: From baseline to 3 months post randomization ]
  Renal Artery Re-intervention
• Number of Participants With Major Bleeding According to TIMI Definition [ Time Frame: From baseline to 3 months post randomization ]
  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).
• Increase in Serum Creatinine [ Time Frame: From baseline to 3 months post randomization ]
  Number of Participants with Increase in Serum Creatinine > 50% from screening visit 2.
• Number of Participants With Hospitalization for Hypertensive Crisis [ Time Frame: From baseline to 3 months post randomization ]
  Hospitalization for Hypertensive Crisis Not Related to Confirmed Nonadherence With Medications or the Protocol
• Change in Office Systolic Blood Pressure [ Time Frame: From baseline to 1 month post procedure ]
  Change in office systolic blood pressure from baseline (Screening Visit 2) to 1-month
• Number of Participants Achieving Target Office Systolic Blood Pressure [ Time Frame: From baseline to 1 month post procedure ]
  Incidence of achieving target office systolic blood pressure (SBP <140 mmHg)
• Number of Participants Achieving Target Office Systolic Blood Pressure [ Time Frame: From baseline to 3 months post procedure ]
  Incidence of Achieving Target Office Systolic Blood Pressure (SBP <140 mmHg)
• Change in Office Diastolic Blood Pressure [ Time Frame: From baseline to 1 month post procedure ]
  Change in office diastolic blood pressure from baseline (Screening Visit 2)
• Change in Office Diastolic Blood Pressure [ Time Frame: From baseline to 3 months post procedure ]
  Change in Office Diastolic Blood Pressure From Baseline (Screening Visit 2) to 3-months
• Change in Diastolic Blood Pressure as Measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM) [ Time Frame: From baseline to 3 months post procedure ]
  Change in diastolic blood pressure from baseline (screening visit 2) to 3-month as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM).

Original Secondary Outcome Measures (submitted: May 6, 2015)

• Change in office systolic blood pressure [ Time Frame: From baseline to 36 months post-procedure ]
• Incidence of achieving target office systolic blood pressure (SBP<140 mmHg or <130 mmHg for patients with diabetes or renal disease) [ Time Frame: From 1 month to 36 months post-procedure ]
• Change in office diastolic blood pressure [ Time Frame: From baseline to 36 months post-procedure ]
• Change in diastolic blood pressure as measured by 24-hour ABPM [ Time Frame: From baseline to 36 months post-procedure ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: SPYRAL PIVOTAL - SPYRAL HTN-OFF MED Study
• Official Title: 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)
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Single (Participant); Primary Purpose: Treatment

Condition

• Hypertension
• Vascular Diseases
• Cardiovascular Diseases

Intervention

• 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
• 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 Name: Renal angiography

Study Arms

• Experimental: Renal Denervation
  Renal angiography and Renal Denervation (Symplicity Spyral™ multi-electrode renal denervation system)
  Intervention: Device: Symplicity Spyral™ multi-electrode renal denervation system
• Sham Comparator: Sham Procedure
  Renal angiography
  Intervention: Procedure: Sham Procedure

Publications *

• 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, Böhm M. Hypertension urgencies in the SPYRAL HTN-OFF MED Pivotal trial. Clin Res Cardiol. 2022 Jul 19. doi: 10.1007/s00392-022-02064-5. [Epub ahead of print]
• Böhm 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, Böhm 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.
• Böhm 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.
• Böhm 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.
• 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.
• Kandzari DE, Kario K, Mahfoud F, Cohen SA, Pilcher G, Pocock S, Townsend R, Weber MA, Böhm 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. Review.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 31, 2020): 366
• Original Estimated Enrollment (submitted: May 6, 2015): 120
• Estimated Study Completion Date: December 2023
• Actual Primary Completion Date: April 30, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 20 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Canada, Germany, Greece, Ireland, Japan, United Kingdom, United States

Administrative Information

• NCT Number: NCT02439749
• Other Study ID Numbers: SPYRAL HTN-OFF MED
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Device Product: Yes
• Device Product Not Approved or Cleared by U.S. FDA: Yes

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Medtronic Vascular
• Original Responsible Party: Same as current
• Current Study Sponsor: Medtronic Vascular
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

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

• PRS Account: Medtronic Vascular
• Verification Date: April 2022