SPYRAL HTN-ON MED Study of Renal Denervation With the Symplicity Spyral™ Multi-electrode Renal Denervation System

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).

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)

Change in office systolic blood pressure from baseline (Screening Visit 2) to 6 months post-procedure

Number of medications from baseline (Screening Visit 2) through 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

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 (SBP<140 mmHg) at 6 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 from baseline (screening visit 2) to 24 months as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM).

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 from baseline (screening visit 2) to 12 months.

Change in office systolic blood pressure from baseline (screening visit 2) to 24 months.

Change in office systolic blood pressure from baseline (screening visit 2) to 36 months.

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 from baseline (screening visit 2) to 24 months as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM).

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 from baseline (screening visit 2) to 12 months.

Change in office diastolic blood pressure from baseline (screening visit 2) to 24 months.

Change in office diastolic blood pressure from baseline (screening visit 2) to 36 months.

Incidence of Achieving Target Office Systolic Blood Pressure (SBP <140 mmHg)

Incidence of Achieving Target Office Systolic Blood Pressure (SBP <140 mmHg).

Incidence of Achieving Target Office Systolic Blood Pressure (SBP <140 mmHg)

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

Renal artery perforation requiring intervention

Number of Participants with Renal artery dissection requiring intervention

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).

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 from baseline (screening visit 2) to 6 months as measured by 24-hour Ambulatory Blood Pressure Monitoring (ABPM).

Change in office diastolic blood pressure from baseline (screening visit 2) 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.

There are no clinically established thresholds. Minimum Value 0; No Maximum value (See Secondary Outcome Measure #5 for comparison)

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.

There are no clinically established thresholds. Minimum Value 0; No Maximum value (See Secondary Outcome Measure #5 for comparison)

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.

There are no clinically established thresholds. Minimum Value 0; No Maximum value (See Secondary Outcome Measure #5 for comparison)