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

The kidneys are an important regulator of blood pressure and it is thought that
in patients whose blood pressure cannot be controlled, there is increased
activity in the nervous system between the brain and kidney which results in
the kidneys releasing an excessive amount (more than normal) of hormones that
raises blood pressure. Medications alone may not be effective in controlling
blood pressure. Previous research has shown that disrupting certain nerves may
decrease blood pressure in some cases. In the past, one technique that was used
to treat severe high blood pressure was a surgical procedure to cut nerves.
However, this surgery is no longer commonly performed, because it was a complex
invasive procedure. This clinical research study will provide additional
information about the safety and effect of renal denervation on blood pressure,
without the confounding presence of antihypertensive medications, using the
Symplicity Spyral* catheter and G3* generator, compaired to a placebocontrolled
group. These data, obtained without the confounding presence of
antihypertensive medications, in conjunction with the data generated in the
companion on medications study (SPYRAL HTN-ON MED), will help determine whether
commonly used antihypertensive medications synergize, antagonize, or have no
impact on the effect of renal denervation on elevated blood pressure. These
data, combined with the data from the SPYRAL HTN-ON MED study, are important
for determining the design of a pivotal renal denervation study.

The objective of this study is to evaluate blood pressure response after renal
denervation in patients with uncontrolled hypertension compared to a
sham-controlled population, in the absence of antihypertensive medications. In
this study, *uncontrolled hypertension* means an office systolic bloodpressure
(SBP) * 150 mmHg and <180 mmHg, an office DBP *90 mmHg and a 24-hour Ambulatory
Blood Pressure Monitoring (ABPM) average SBP *140 mmHg to <170 mmHg measured at
Screening Visit 2. These data, without the confounding presence of
antihypertensive medications, in conjunction with the data generated in the
companion study (SPYRAL HTN-ON MED), will help determine whether commonly used
antihypertensive medications synergize, antagonize, or have no impact on the
effect of renal denervation on elevated blood pressure. These data, combined
with the data from the SPYRAL HTN-ON MED study, are important for determining
the design of a pivotal renal denervation study.

The SPYRAL HTN-OFF MED study is a multi-center, international, prospective,
single blinded,randomized, interventional, sham-controlled study.
See CIP page 41, Figure 8: Study Design Overview

Following Screening Visit 1 (SV1), eligible subjects will undergo a minimum of
three and a maximum of four weeks antihypertensive medication washout period.
If at any time the average of 3 seated office readings results in a SBP *180
mmHg, the subject will be considered a screen failure. If the SBP remains *180
mmHg, the subject will be exited from the study and antihypertensive medication
started at the investigator*s discretion. Subjects who continue to meet
eligibility criteria will return for

Screening Visit 2 (SV2). Subjects who were not previously treated with
antihypertensive medications will also return for Screening Visit 2 within
three to four weeks. Subjects who continue to meet eligibility criteria after
completion of Screening Visit 2 and who have received randomization approval by
the Sponsor will be randomized. The renal denervation or control procedure will
occur within a maximum of two weeks following completion of Screening Visit 2.
All efforts should be undertaken to schedule the procedure within one week of
Screening Visit 2.

Following the renal denervation or control procedure, subjects will be followed
at 2, 4, 6, 8, 10 and 12 weeks post-procedure. At any time, if the subject*s
office SBP *180 mmHg as measured per protocol with a confirmatory BP
measurement within 72 hours, the subject can be put back on an antihypertensive
medication regimen per the investigator*s discretion. If possible but at the
discretion of the physician, the subject will be asked to wear an ABPM and have
blood drawn for a Chem 7panel prior to being put back on medications. The
subject will then be exited from the off medications portion of the study and
will be followed.

At the three months follow-up, after office and ambulatory blood pressure
measurements are obtained, subjects will be titrated back onto standard medical
therapy. All subjects will return for follow-up at 6 months and 12 months.
Subjects and blinded study personnel will be unblinded to the
randomization assignment at 12 months. Subjects randomized to renal denervation
will continue to be followed annually through 36 months post-procedure.
Subjects randomized to the control group will not be required to return
annually for office visits, but will be contacted by phone at 24 and
36 months to obtain vital status, anti-hypertensive medications
prescribed/taking, and SAEs only.

After the study blinded period (i.e., 12-Month subject follow-up visits are
completed), the study sponsor will review preliminary study data. If the
outcomes in the Denervation Group are considered to be positive as determined
by the study sponsor in consultation with the study Executive Steering
Committee and Site Investigator, control subjects may be offered renal
denervation therapy (crossover) after meeting key inclusion criteria and no key
exclusion criteria. In this case, crossover subjects will return for office
visits at 1, 6, 12 and 24 months post-renal denervation procedure.

Although no assurances or guarantees can be made, there is a reasonable
expectation that the renal denervation procedure may be beneficial to the
subject. Treatment with the Medtronic Symplicity Spyral* multi-electrode renal
denervation catheter and the Symplicity G3TM renal denervation RF generator may
reduce the nerve activity to and from the kidneys, and cause a reduction in
blood pressure.
Evidence in the literature suggests that reduction of efferent sympathetic
nerve activity to the kidney can
a) cause relief of renal vasoconstriction, resulting in improved kidney
function;
b) reduce sodium retention, which can improve the clinical condition of
patients with medical problems related to excess salt and water;
c) reduce the release of renin - a renal produced hormone which is often
elevated in patients with either severe hypertension or heart failure.
Interference of afferent nerve activity from the kidneys can reduce central
sympathetic activity, also causing reduction of blood pressure.
A reduction in blood pressure may result in the decrease or elimination of any
symptoms associated with high blood pressure and/or reduction of blood pressure
medications and the side effects related to medications. In addition, reduction
in blood pressure may decrease the risk of other related adverse events
associated with high blood pressure (risk of stroke, heart attack, renal
failure, etc.). See for more information J1 of the CIP


The primary risks of the renal denervation procedure are similar to the risks
of all diagnostic procedures requiring catheterization of the arteries of the
body. Below a few potential risks of the catheterization procedure (including
renal angiogram) more information can be found in J2 of the CIP:
- Death * a complication or deterioration of health ultimately leading to a
patient*s death.
- Cardiopulmonary arrest * cessation of blood circulation and/or respiration
due to
dysfunction of the heart and/or lungs.
- Heart rhythm disturbances * disruption of normal heart rate or rhythm,
including
bradycardia treated with atropine.
- Embolism * formation and dislodgement of a blood clot (thrombus) or
dislodgement of
cholesterol/plaque within the blood vessel, which travels downstream into small
vessels,
blocking blood flow and causing temporary or permanent damage to organs distal
to
blockage. Emboli are known to cause myocardial infarction, stroke or kidney
damage,
peripheral ischemia and may ultimately lead to incapacitation or death.
- Complications at catheter insertion site in the groin:
o Pain * discomfort at the catheter insertion site that can range from mild to
severe.
o Hematoma/Bruising * a collection of blood in the tissue surrounding the
catheter
insertion site.
o Pseudoaneurysm * a collection of blood in the tissue surrounding the catheter
insertion site due to ongoing leaking of blood from a blood vessel.
o AV fistula * an abnormal connection between an artery and a vein (i.e., caused
by needle insertion through the femoral artery and vein).
o Infection * localized redness, heat swelling and pain at the catheter
insertion site,
o Significant bleeding * blood loss from the catheter insertion site requiring
surgery
or transfusion of 2 or more units of packed red blood cells (PRBCs).
* Retroperitoneal bleeding * bleeding into the retroperitoneal space.
* Vascular complications requiring surgery * damage to an artery (e.g.,
femoral) or vein
requiring surgical repair.
* Perforation of a blood vessel * unintended puncture through the wall of a
blood vessel,
such as a renal artery, requiring repair.

More information can be found in J2 of the CIP