Hypertension
Conditions
Keywords
Hypertension, High Blood Pressure, Blood Pressure, Cardiovascular Disease, Resistant Hypertension, Stage 2 Hypertension, Hypertension that is resistant to treatment
Brief summary
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.
Interventions
DEVICERheos® Baroreflex Hypertension System
Electrical activation of the Carotid Baroreflex
Sponsors
CVRx, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 80 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Serious Procedure- or System-related Adverse Event-free Rate in Both Implanted and Attempted Patients | 30 days post implant | 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. |
| Percent of Patients With a 10mmHg or Greater Reduction in Office Cuff Systolic Blood Pressure | 6 months post-activation | 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%. |
| 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. | 12 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. |
| Major Hypertension-related and Serious Device-related Adverse Event-Free Rate in Both Implanted and Attempted Patients. | 12 months-post activation | 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. |
| Therapy-related Adverse Event-free Rate. | 6 months post-activation | 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%. |
Countries
Germany, Netherlands, United States
Participant flow
Pre-assignment details
Of the 591 patients enrolled, 78 withdrew prior to implant and 187 screen-failed. 4 implants were unsuccessful, and 2 randomized patients were terminated prior to the randomization visit. 55 patients were roll-in patients that were not randomized. A total of 265 patients were both randomized and implanted.
Participants by arm
| Arm | Count |
|---|---|
| Roll-In Subjects that were not included in endpoint analyses | 55 |
| Rheos® Device 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.
Rheos® Baroreflex Hypertension System: Electrical activation of the Carotid Baroreflex | 181 |
| Rheos® Device 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.
Rheos® Baroreflex Hypertension System: Electrical activation of the Carotid Baroreflex | 84 |
| Total | 320 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Patient Injury | 1 | 0 |
| Overall Study | System explanted | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Rheos® Device Off | Total | Roll-In | Rheos® Device On |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 48 Participants | 9 Participants | 30 Participants |
| Age, Categorical Between 18 and 65 years | 75 Participants | 272 Participants | 46 Participants | 151 Participants |
| Race/Ethnicity, Customized African American | 18 Participants | 59 Participants | 11 Participants | 30 Participants |
| Race/Ethnicity, Customized Hispanic | 4 Participants | 9 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 7 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized White/Caucasian | 59 Participants | 245 Participants | 40 Participants | 146 Participants |
| Region of Enrollment Germany | 5 participants | 13 participants | 0 participants | 8 participants |
| Region of Enrollment Netherlands | 5 participants | 13 participants | 0 participants | 8 participants |
| Region of Enrollment United States | 74 participants | 294 participants | 55 participants | 165 participants |
| Sex: Female, Male Female | 38 Participants | 127 Participants | 24 Participants | 65 Participants |
| Sex: Female, Male Male | 46 Participants | 193 Participants | 31 Participants | 116 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 75 / 181 | 39 / 84 |
| serious Total, serious adverse events | 102 / 181 | 45 / 84 |
Outcome results
Primary
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.
Time frame: 12 months-post activation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rheos® Device On | Major Hypertension-related and Serious Device-related Adverse Event-Free Rate in Both Implanted and Attempted Patients. | 87.2 percentage of participants |
Primary
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.
Time frame: 12 months post-activation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rheos® Device On | 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. | 87.6 percentage of participants |
Primary
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%.
Time frame: 6 months post-activation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rheos® Device On | Percent of Patients With a 10mmHg or Greater Reduction in Office Cuff Systolic Blood Pressure | 54.1 percentage of participants |
| Rheos® Device Off | Percent of Patients With a 10mmHg or Greater Reduction in Office Cuff Systolic Blood Pressure | 46.4 percentage of participants |
Primary
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.
Time frame: 30 days post implant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rheos® Device On | Serious Procedure- or System-related Adverse Event-free Rate in Both Implanted and Attempted Patients | 74.8 percentage of participants |
Primary
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%.
Time frame: 6 months post-activation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rheos® Device On | Therapy-related Adverse Event-free Rate. | 91.7 percentage of participants |
| Rheos® Device Off | Therapy-related Adverse Event-free Rate. | 89.3 percentage of participants |