Rheos® Pivotal Trial

Rheos® Pivotal Trial: Rheos™ Baroreflex Hypertension Therapy System

The purpose of this clinical trial is to demonstrate the efficacy and safety of the Rheos system in subjects with hypertension that are resistant to treatment with at least three anti-hypertension agents, one of which is a diuretic.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Device: Rheos® Baroreflex Hypertension System

• Study Type: Interventional
• Enrollment (Actual): 591
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Germany
  • Hannover, Germany
    • Medizinische Hochschule Hannover
• Netherlands
  • Maastricht, Netherlands
    • University Hospital Maastricht
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • California
    • Inglewood, California, United States, 90301
      • Apex Cardiology
    • Los Angeles, California, United States, 90033
      • University of Southern California
    • Orange, California, United States, 92868
      • St Joseph Health
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • George Washington University Hospital
    • Washington, District of Columbia, United States, 20422
      • VA Medical Center
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Jacksonville Center for Clinical Research
    • Orlando, Florida, United States, 32803
      • Florida Hospital Cardiovascular Institute
    • Pensacola, Florida, United States, 32504
      • Pensacola Research Consultants
    • St. Petersburg, Florida, United States, 33709
      • The Heart And Vascular Institute Of Florida
    • Tampa, Florida, United States, 33609
      • Florida Cardiovascular Institute
  • Georgia
    • Columbus, Georgia, United States, 31904
      • Southeast Regional Research Group
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago, Dept. of Medicine, Section of Endocinology, Diabetes & Metabolism
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • The Care Group
  • Iowa
    • West Des Moines, Iowa, United States, 50266
      • Iowa Heart Center
  • Kansas
    • Shawnee Mission, Kansas, United States, 66204
      • The Center for Cardiovascular Studies, LLC
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Womens Hospital
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • St.Louis, Missouri, United States, 63110
      • Washington University
  • Nebraska
    • Lincoln, Nebraska, United States, 68526
      • Nebraska Heart Institute
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • Rochester, New York, United States, 14623
      • University of Rochester
  • North Carolina
    • Raleigh, North Carolina, United States, 27607
      • Rex Healthcare
    • Winston-Salem, North Carolina, United States, 27103
      • Forsyth Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • The Lindner Clinical Trial Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
    • Columbus, Ohio, United States, 43210
      • Ohio State Medical Center
    • Toledo, Ohio, United States, 43606
      • Jobst Vascular Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73120
      • Oklahoma Foundation for Cardiovascular Research
  • Pennsylvania
    • Lancaster, Pennsylvania, United States, 17604
      • Lancaster General Hospital
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Health System
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57104
      • Sanford Clinical Research
  • Tennessee
    • Knoxville, Tennessee, United States, 37920
      • Clinical Research Solutions, P.C.
    • Nashville, Tennessee, United States, 37205
      • Saint Thomas Research Institute
  • Texas
    • Houston, Texas, United States, 77030
      • The Methodist Hospital Research Institute
    • Temple, Texas, United States, 76508
      • Scott and White Memoral Hospital
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98122
      • Swedish Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Be at least 21 years of age and no more than 80 years of age.
• Have been assessed with bilateral carotid bifurcations that are easily interrogated by carotid duplex ultrasound and are below the level of the mandible.
• Office cuff systolic blood pressure greater than or equal to 160 mmHg and have a diastolic blood pressure greater than or equal to 80 mmHg as well as a 24-hour ambulatory systolic blood pressure greater than or equal to 135 mmHg despite at lest one month of maximally tolerated therapy with at least three anti-hypertensive medications, of which at least one must be a diuretic.
• Must have completed the drug compliance questionnaire and have been judged to be compliant with medications.
• For subjects that have had prior bariatric surgery, they must be at least 1 year post-surgery and at a stable weight.
• If female, the subject must be surgically sterile, or using a medically accepted method of birth control and agree to continue use of this method for the duration of the trial. Women of childbearing potential must have a negative serum pregnancy test in the pre-implant blood evaluation.
• Must be an appropriate or reasonable surgical candidate.
• Have signed a CVRx approved informed consent form for participation in this study

Exclusion Criteria:

• Have known or suspected baroreflex failure or autonomic neuropathy.
• Have an arm circumference greater than 46 cm and/or body mass index of greater than 45.
• Have significant cardiac bradyarrhythmias.
• Have chronic atrial fibrillation.
• Have significant orthostatic hypotension
• Had a solid organ or hematologic transplant.
• Had a myocardial infarction, unstable angina, syncope, or cerebral vascular accident within the past 3 months.
• Have carotid atherosclerosis producing a 50% or greater reduction in linear diameter as determined by ultrasound or angiographic evaluation as determined within 6 months of enrollment in the trial.
• Have ulcerative plaques in the carotid artery as determined by ultrasound or angiographic evaluation.
• Have prior surgery, radiation, or endovascular stent placement in either carotid sinus region.

• Have severe chronic kidney disease as defined by:

  • Currently undergoing dialysis or dialysis is planned within 3 months of the implant date
  • eGFR of ≤30 ml/min/1.73m²
• Have hypertension secondary to an identifiable and treatable cause other than sleep apnea.
• Have clinically significant cardiac structural valvular disease.
• Have clinically significant reactive airway disease, chronic obstructive pulmonary disease, and/or primary pulmonary hypertension.
• Have an uncontrolled comorbid medical condition that would adversely affect participation in the trial.
• Have a clinically significant psychological illness that would prohibit the subject's ability to meet the protocol requirements
• Are currently taking an imidazolone receptor agonist
• Are unable or unwilling to fulfill the protocol medication compliance and follow-up requirements.
• Have an active infection within the last month.
• Have a co-morbid condition that reduces life expectancy to less than one year.
• Are enrolled in another concurrent clinical trial, without prior approval of CVRx.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: On; Subject will be randomized to a 2:1 allocation to the Rheos ON or OFF arms at the time of Rheos System activation (time point 0). After the six month follow up evaluation, all subjects will have therapy activated, though subjects and treating physicians will not be informed of randomized treatment assignment.	Device: Rheos® Baroreflex Hypertension System; Electrical activation of the Carotid Baroreflex
Experimental: Off; Subject will be randomized to a 2:1 allocation to the Rheos ON or OFF arms at the time of Rheos System activation (time point 0). After the six month follow up evaluation, all subjects will have therapy activated, though subjects and treating physicians will not be informed of randomized treatment assignment.	Device: Rheos® Baroreflex Hypertension System; Electrical activation of the Carotid Baroreflex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent of Patients With a 10mmHg or Greater Reduction in Office Cuff Systolic Blood Pressure	Compare Group A (Rheos® Device On ) versus Group B (Rheos® Device Off) via a double-blind, randomized, parallel group, super-superiority design for proportion of subjects that achieve at least a 10 mm Hg drop in systolic blood pressure at Month 6 compared to Month 0, with a superiority margin of 20%.	6 months post-activation
Percent of Group A (Rheos® Device On) Patients Who Maintain a 10 mm Hg Drop in Systolic Blood Pressure at 12 Months Post-activation, and Whose Response at 12 Months is at Least 50% of the Response Observed at 6 Months Post-activation.	Compare the sustained response in SBP Month 12 in Group A ( Rheos® Device On ) responders at Month 6 to an objective performance criterion of 65%. A sustained response to therapy required the reduction from Month 0 to Month 12 to be at least 10 mmHg and to remain at least 50% of that seen at Month 6.	12 months post-activation
Serious Procedure- or System-related Adverse Event-free Rate in Both Implanted and Attempted Patients	Compare the serious procedure- or system-related adverse event-free rate for events occurring within 30 days of implant to a pre-specified objective performance criterion of 82% set based on historical literature on implantable cardioverter defibrillators (ICD) and pacemakers. Note: The purpose of this outcome measure was to evaluate the effect of having the device implanted, not to compare the outcomes between the two treatment groups. Therefore, both groups were analyzed as a single cohort.	30 days post implant
Major Hypertension-related and Serious Device-related Adverse Event-Free Rate in Both Implanted and Attempted Patients.	Compare the event-free rate for all major hypertension-related and serious device-related adverse events occurring between 30 days post-implant and the Month 12 visit, to a pre-specified objective performance criterion of 72% based on similar implantable devices such as defibrillators and resynchronization devices. Note: The purpose of this outcome measure was to evaluate the effect of having the device implanted, not to compare the outcomes between the two treatment groups. Therefore, both groups were analyzed as a single cohort.	12 months-post activation
Therapy-related Adverse Event-free Rate.	Compare Group A (Rheos® Device On ) versus Group B (Rheos® Device Off) therapy-related adverse event-free rates via a double-blind, randomized, parallel group, non-inferiority design for therapy-related serious adverse events occurring between 30 days post-implant and the Month 6 visit. The non-inferiority margin was 15%.	6 months post-activation

Collaborators and Investigators

• Sponsor: CVRx, Inc.
• Investigators: Principal Investigator: Mitra Nadim, MD, University of Southern California

Publications and helpful links

General Publications

• Wachter R, Halbach M, Bakris GL, Bisognano JD, Haller H, Beige J, Kroon AA, Nadim MK, Lovett EG, Schafer JE, de Leeuw PW. An exploratory propensity score matched comparison of second-generation and first-generation baroreflex activation therapy systems. J Am Soc Hypertens. 2017 Feb;11(2):81-91. doi: 10.1016/j.jash.2016.12.003. Epub 2016 Dec 16.
• de Leeuw PW, Alnima T, Lovett E, Sica D, Bisognano J, Haller H, Kroon AA. Bilateral or unilateral stimulation for baroreflex activation therapy. Hypertension. 2015 Jan;65(1):187-92. doi: 10.1161/HYPERTENSIONAHA.114.04492. Epub 2014 Oct 20.

Helpful Links

• Additional information about the Rheos Pivotal Trial for patients and medical professionals can be found at http://www.bloodpressuretrial.com/

Study record dates

Study Major Dates

• Study Start: October 1, 2006
• Primary Completion (Actual): January 1, 2016
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: February 27, 2007
• First Submitted That Met QC Criteria: February 28, 2007
• First Posted (Estimate): March 1, 2007

Study Record Updates

• Last Update Posted (Actual): March 20, 2017
• Last Update Submitted That Met QC Criteria: January 30, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: Hypertension; Cardiovascular Disease; Blood Pressure; Resistant Hypertension; High Blood Pressure; Stage 2 Hypertension; Hypertension that is resistant to treatment
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension
• Other Study ID Numbers: 360009