Cardiovascular Diseases, Hypertension, Vascular Diseases
Conditions
Keywords
Uncontrolled hypertension, Renal denervation
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 presence of up to three standard antihypertensive medications.
Detailed description
The purpose of this study is to test the hypothesis that renal denervation is safe and reduces systolic blood pressure (SBP) in patients with uncontrolled hypertension on one, two, or three standard antihypertensive medications compared to a sham control in the same population. In this study, "uncontrolled hypertension" is defined as an office systolic blood pressure (SBP) ≥ 150 mmHg and \<180 mmHg, an office Diastolic Blood Pressure (DBP) ≥90 mmHg and a 24-hour Ambulatory Blood Pressure Monitoring (ABPM) average SBP ≥140 mmHg to \<170 mmHg, all of which are measured at Screening Visits. Data obtained will be used to confirm the effect of renal denervation on elevated blood pressure in patients on 1, 2 or 3 antihypertensive medications.
Interventions
After a renal angiography according to standard procedures, subjects remain blinded and are immediately treated with the renal denervation procedure after randomization.
PROCEDURESham 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.
Sponsors
Medtronic Vascular
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Individual has office systolic blood pressure (SBP) ≥ 150 mmHg and \<180 mmHg and a diastolic blood pressure (DBP) ≥ 90 mmHg when receiving a medication regimen of one, two, or three antihypertensive medication classes. * Individual has 24-hour Ambulatory Blood Pressure Monitoring (ABPM) average SBP ≥ 140 mmHg and \< 170 mmHg.
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Systolic Blood Pressure as Measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM) | From baseline to 6 months post-procedure | Baseline adjusted change (using Analysis of Covariance) in systolic blood pressure (SBP) from baseline (Screening Visit 2) to 6 months post-procedure as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM). |
| Acute and Chronic Safety by Evaluating Incidence of Major Adverse Events | From Baseline to 1 month post-procedure (6 months for new renal artery stenosis) | The Primary safety endpoint of the study is the incidence of Major Adverse Events (MAE), defined as composite of the following 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%, confirmed by angiography and as determined by the angiographic core laboratory, through one-month post-randomization (6-months for new renal artery stenosis) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Office Systolic Blood Pressure to 6-months | From baseline to 6 months post-procedure | Change in office systolic blood pressure from baseline (Screening Visit 2) to 6 months post-procedure |
| Antihypertensive Medication Usage and Changes to 6-months | From baseline to 6-month post-procedure | Number of medications from baseline (Screening Visit 2) through 6 Months post-procedure |
| Antihypertensive Medication Burden to 6-months | From baseline to 6 Months post-procedure | Based on the prescribed medications reported, medication burden was calculated using Medication Index 2 score which is a composite index based on the doses of antihypertensive medications multiplied by the number of medications prescribed; all classes (ACE/ARB, calcium channel blockers, etc.) were considered equivalent in potency. Higher score indicates higher dosages being prescribed over the standard dose. Minimum value 0; No Maximum value |
| Medication Changes | Baseline to 6-months post-procedure | Patients who had medication changes based on Medication Index 2 drug testing data. Medication Index 2 score is a composite index based on the doses of antihypertensive medications multiplied by the number of medications prescribed; all classes (ACE/ARB, calcium channel blockers, etc.) were considered equivalent in potency. |
| Incidence of Achieving Target Office Systolic Blood Pressure | From baseline to 6 months post-procedure | Incidence of achieving target office systolic blood pressure (SBP\<140 mmHg) at 6 months post- procedure. |
| Change in Systolic Blood Pressure as Measured by 24-hour ABPM 12 Months | From Baseline to 12 months post procedure | Change in systolic blood pressure from baseline (screening visit 2) to 12 months as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM) |
| Change in Systolic Blood Pressure as Measured by 24-hour ABPM 24-months | From baseline to 24 months post-procedure | Change in systolic blood pressure from baseline (screening visit 2) to 24 months as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM). |
| Change in Systolic Blood Pressure as Measured by 24-hour ABPM 36-months | From baseline to 36 months post-procedure | Change in systolic blood pressure from baseline (screening visit 2) to 36 months as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM). |
| Change in Office Systolic Blood Pressure to 12-months | From Baseline to 12 months post procedure | Change in office systolic blood pressure from baseline (screening visit 2) to 12 months. |
| Change in Office Systolic Blood Pressure to 24-months | From baseline to 24 months post-procedure | Change in office systolic blood pressure from baseline (screening visit 2) to 24 months. |
| Change in Office Systolic Blood Pressure to 36-months | From baseline to 36 months post-procedure | Change in office systolic blood pressure from baseline (screening visit 2) to 36 months. |
| Change in Diastolic Blood Pressure as Measured by 24-hour ABPM 12-months | From Baseline to 12 months post procedure | Change in diastolic blood pressure from baseline (screening visit 2) to 12 months as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM). |
| Change in Diastolic Blood Pressure as Measured by 24-hour ABPM 24-months | From baseline to 24 months post-procedure | Change in diastolic blood pressure from baseline (screening visit 2) to 24 months as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM). |
| Change in Diastolic Blood Pressure as Measured by 24-hour ABPM 36-months | From baseline to 36 months post-procedure | Change in diastolic blood pressure from baseline (screening visit 2) to 36 months as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM). |
| Change in Office Diastolic Blood Pressure 12 Months | From baseline to 12 months post-procedure | Change in office diastolic blood pressure from baseline (screening visit 2) to 12 months. |
| Change in Office Diastolic Blood Pressure 24 Months | From baseline to 24 months post-procedure | Change in office diastolic blood pressure from baseline (screening visit 2) to 24 months. |
| Change in Office Diastolic Blood Pressure 36 Months | From baseline to 36 months post-procedure | Change in office diastolic blood pressure from baseline (screening visit 2) to 36 months. |
| Number of Participants Achieving Target Office Systolic Blood Pressure 12 Months | From baseline to 12 months post-procedure | Incidence of Achieving Target Office Systolic Blood Pressure (SBP \<140 mmHg) |
| Number of Participants Achieving Target Office Systolic Blood Pressure 24 Months | From baseline to 24 months post-procedure | Incidence of Achieving Target Office Systolic Blood Pressure (SBP \<140 mmHg). |
| Number of Participants Achieving Target Office Systolic Blood Pressure. 36 Months | From baseline to 36 months post-procedure | Incidence of Achieving Target Office Systolic Blood Pressure (SBP \<140 mmHg) |
| Number of Participants With All Cause Mortality | From Baseline to 36-months post procedure | — |
| Number of Participants With End-Stage Renal Disease (ESRD) | From Baseline to 36-months post-procedure | 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 |
| Number of Participants With Significant Embolic Event Resulting in End-organ Damage | From Baseline to 36 months post-procedure | — |
| Number of Participants With Renal Artery Perforation Requiring Intervention | From Baseline to 36 month post-procedure | Renal artery perforation requiring intervention |
| Number of Participants With Renal Artery Dissection Requiring Intervention | From Baseline to 36 months post-procedure | Number of Participants with Renal artery dissection requiring intervention |
| Number of Participants With Vascular Complications | From Baseline to 36 months 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 Hospitalization for Hypertensive Crisis Not Related to Confirmed Non-adherence With Medications and/or the Protocol. | From Baseline to 36 months 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 36 months post-procedure | — |
| Number of Participants With ≥ 40% Decline in eGFR | From baseline to 36 months post-procedure | — |
| Number of Participants With Increase in Serum Creatinine >50% From Screening Visit 2 (Baseline) | From baseline to 36 months post-procedure | — |
| Number of Participants With New Myocardial Infarct | From baseline to 36 months post-procedure | — |
| Number of Participants With New Stroke | From baseline to 36 months post-procedure | — |
| Number of Participants With Renal Artery Re-intervention | From baseline to 36 months post-procedure | — |
| Number of Participants With Major Bleeding According to TIMI Definition | From baseline to 36 months 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 |
| Change in Diastolic Blood Pressure as Measured by 24-hour (ABPM) 6-months | From baseline to 6 months post-procedure | Change in diastolic blood pressure from baseline (screening visit 2) to 6 months as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM). |
| Change in Office Diastolic Blood Pressure to 6-months | From baseline to 6 months post-procedure | Change in office diastolic blood pressure from baseline (screening visit 2) to 6 months post-procedure |
Countries
Australia, Austria, Canada, France, Germany, Greece, Ireland, Japan, United Kingdom, United States
Contacts
PRINCIPAL_INVESTIGATORRaymond Townsend, MD
University of Pennsylvania
PRINCIPAL_INVESTIGATORDavid Kandzari, MD
Piedmont Hospital
PRINCIPAL_INVESTIGATORMichael Böhm, MD
Universitätskliniken des Saarlandes
PRINCIPAL_INVESTIGATORKazuomi Kario, MD
Jichi Medical University
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Renal Denervation Renal angiography and Renal Denervation (Symplicity Spyral™ multi-electrode renal denervation system)
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. | 206 |
| Sham Procedure Renal angiography
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. | 131 |
| Total | 337 |
Baseline characteristics
| Characteristic | Total | Renal Denervation | Sham Procedure |
|---|---|---|---|
| 24- hour Ambulatory Blood Pressure 24-hour Ambulatory Diastolic Blood Pressure | 96.2 mm Hg STANDARD_DEVIATION 7.65 | 96.6 mm Hg STANDARD_DEVIATION 7.6 | 95.7 mm Hg STANDARD_DEVIATION 7.7 |
| 24- hour Ambulatory Blood Pressure 24- hour Ambulatory Systolic Blood Pressure | 149.5 mm Hg STANDARD_DEVIATION 7 | 149.6 mm Hg STANDARD_DEVIATION 7 | 149.3 mm Hg STANDARD_DEVIATION 7 |
| Age, Continuous | 54.9 Years STANDARD_DEVIATION 9.2 | 55.2 Years STANDARD_DEVIATION 9 | 54.6 Years STANDARD_DEVIATION 9.4 |
| Length of hypertension diagnosis 0-5 years | 86 Participants | 62 Participants | 24 Participants |
| Length of hypertension diagnosis >10 years | 187 Participants | 107 Participants | 80 Participants |
| Length of hypertension diagnosis 6-10 years | 64 Participants | 37 Participants | 27 Participants |
| Office Blood Pressure Office Diastolic Blood Pressure | 101.4 mm Hg STANDARD_DEVIATION 7.2 | 101.2 mm Hg STANDARD_DEVIATION 7 | 101.5 mm Hg STANDARD_DEVIATION 7.3 |
| Office Blood Pressure Office Systolic Blood Pressure | 163.05 mm Hg STANDARD_DEVIATION 7.8 | 163.0 mm Hg STANDARD_DEVIATION 7.7 | 163.1 mm Hg STANDARD_DEVIATION 7.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 27 Participants | 17 Participants | 10 Participants |
| Race (NIH/OMB) Black or African American | 60 Participants | 35 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 129 Participants | 81 Participants | 48 Participants |
| Race (NIH/OMB) White | 119 Participants | 71 Participants | 48 Participants |
| Sex: Female, Male Female | 67 Participants | 39 Participants | 28 Participants |
| Sex: Female, Male Male | 270 Participants | 167 Participants | 103 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 206 | 1 / 131 |
| other Total, other adverse events | 148 / 206 | 96 / 131 |
| serious Total, serious adverse events | 51 / 206 | 26 / 131 |
Outcome results
Primary
Acute and Chronic Safety by Evaluating Incidence of Major Adverse Events
The primary safety endpoint of the study is the incidence of Major Adverse Events (MAE), defined as a composite of the following 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%, confirmed by angiography and as a determined by the angiographic core laboratory, through one-month post-randomization (6- months for new renal artery stenosis).
Time frame: From baseline to 1 month post-procedure (6 months for new renal artery stenosis)
Population: All randomized subjects are analyzed according to their randomized treatment.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Renal Denervation | Acute and Chronic Safety by Evaluating Incidence of Major Adverse Events | No MAE | 204 Participants |
| Renal Denervation | Acute and Chronic Safety by Evaluating Incidence of Major Adverse Events | Vascular Complication requiring intervention | 2 Participants |
| Sham Procedure | Acute and Chronic Safety by Evaluating Incidence of Major Adverse Events | No MAE | 130 Participants |
| Sham Procedure | Acute and Chronic Safety by Evaluating Incidence of Major Adverse Events | Vascular Complication requiring intervention | 1 Participants |
Primary
Change in Systolic Blood Pressure as Measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM)
Baseline adjusted change (using Analysis of Covariance) in systolic blood pressure (SBP) from baseline (Screening Visit 2) to 6 months post-procedure as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM).
Time frame: From baseline to 6 months post-procedure
Population: All randomized subjects are analyzed according to their randomized treatment. Subjects who met the anti-hypertensive medication escape criteria (Office SBP\>180 or \<115 mmHg associated with symptoms of hypotension or safety concern requiring medication changes) are analyzed using Last Observation Carried Forward (LOCF) for their blood pressure measurements out to 6-months.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Renal Denervation | Change in Systolic Blood Pressure as Measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM) | -6.5 mm Hg | Standard Deviation 10.7 |
| Sham Procedure | Change in Systolic Blood Pressure as Measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM) | -4.5 mm Hg | Standard Deviation 10.3 |
p-value: 0.1194ANCOVA
Secondary
Antihypertensive Medication Burden to 6-months
Based on the prescribed medications reported, medication burden was calculated using Medication Index 2 score which is a composite index based on the doses of antihypertensive medications multiplied by the number of medications prescribed; all classes (ACE/ARB, calcium channel blockers, etc.) were considered equivalent in potency. Higher score indicates higher dosages being prescribed over the standard dose. Minimum value 0; No Maximum value
Time frame: From baseline to 6 Months post-procedure
Population: Prescribed medications reported
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Renal Denervation | Antihypertensive Medication Burden to 6-months | Baseline | 2.8 Medication Index 2 Score | Standard Deviation 2.5 |
| Renal Denervation | Antihypertensive Medication Burden to 6-months | 6 Months | 2.9 Medication Index 2 Score | Standard Deviation 2.7 |
| Sham Procedure | Antihypertensive Medication Burden to 6-months | Baseline | 3.0 Medication Index 2 Score | Standard Deviation 2.6 |
| Sham Procedure | Antihypertensive Medication Burden to 6-months | 6 Months | 3.5 Medication Index 2 Score | Standard Deviation 3.2 |
Secondary
Antihypertensive Medication Usage and Changes to 6-months
Number of medications from baseline (Screening Visit 2) through 6 Months post-procedure
Time frame: From baseline to 6-month post-procedure
Population: Prescribed daily medication reported
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Renal Denervation | Antihypertensive Medication Usage and Changes to 6-months | Baseline | 1.9 Number of Daily Medications | Standard Deviation 0.8 |
| Renal Denervation | Antihypertensive Medication Usage and Changes to 6-months | 6 Months | 1.9 Number of Daily Medications | Standard Deviation 0.9 |
| Sham Procedure | Antihypertensive Medication Usage and Changes to 6-months | Baseline | 1.9 Number of Daily Medications | Standard Deviation 0.8 |
| Sham Procedure | Antihypertensive Medication Usage and Changes to 6-months | 6 Months | 2.1 Number of Daily Medications | Standard Deviation 0.9 |
Secondary
Change in Office Systolic Blood Pressure
Change in office systolic blood pressure from baseline (Screening Visit 2) to 6 months post-procedure
Time frame: From baseline to 6 months post-procedure
Population: Valid readings at time of data collection
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Renal Denervation | Change in Office Systolic Blood Pressure | -9.9 mmHg | Standard Deviation 13.9 |
| Sham Procedure | Change in Office Systolic Blood Pressure | -5.1 mmHg | Standard Deviation 13.2 |
Secondary
Incidence of Achieving Target Office Systolic Blood Pressure
Incidence of achieving target office systolic blood pressure (SBP\<140 mmHg) at 6 months post- procedure.
Time frame: From baseline to 6 months post-procedure
Population: Valid readings at time of data collection
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Renal Denervation | Incidence of Achieving Target Office Systolic Blood Pressure | 39 Participants |
| Sham Procedure | Incidence of Achieving Target Office Systolic Blood Pressure | 8 Participants |
Secondary
Medication Changes
Patients who had medication changes based on Medication Index 2 drug testing data. Medication Index 2 score is a composite index based on the doses of antihypertensive medications multiplied by the number of medications prescribed; all classes (ACE/ARB, calcium channel blockers, etc.) were considered equivalent in potency.
Time frame: Baseline to 6-months post-procedure
Population: Confirmed via Drug Testing Data at both Baseline (Screening Visit 2) and 6-months post-procedure
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Renal Denervation | Medication Changes | Increase | 37 Participants |
| Renal Denervation | Medication Changes | No Change | 131 Participants |
| Renal Denervation | Medication Changes | Decrease | 32 Participants |
| Sham Procedure | Medication Changes | Increase | 35 Participants |
| Sham Procedure | Medication Changes | No Change | 80 Participants |
| Sham Procedure | Medication Changes | Decrease | 13 Participants |