1. SMART Study: Sympathetic Mapping/Ablation of Renal Nerves Trial
----- SyMap Technology Update
Jie Wang, MD, PhD
Jiangsu Province Hospital
Nanjing, China
Columbia University, USA

2. Disclosure J Wang is a co-founder of SyMap Medical Ltd
consultant to Coridea, Park Medical

3. Why SYMPLICITY III Missed Its Efficacy Endpoint
Procedure-related factors: Device-related Issue
Drug changes/drug adherence
Patient population
Patients-related
Issue 3

4. To Address Device-related Issue:
Our Solution
Unique 5-in-1 Catheter/Stimulator/
RF Generator
· Systemic Blood Pressure
· Heart Rate
· Unique 5-in-1 Catheter/
Stimulator/RF Generator 4

5. Novel Catheter and Stimulator/RF Generator

6. To Address Patients-related Issue:
Our Solution
Drug Resistant Hypertension Patients?
“Real World” Patients (Anti-hypertensive drug therapy for at least 6m, SBP ≧150mmHg, SDP ≧100mmHg)? 6

7. Sympathetic Mapping/Ablation of Renal Nerves Trial
A Prospective, Multicenter, Single Blind, Randomized and Controlled Trial of Renal Sympathetic Denervation Using SyMapCath I™ Catheter and SYMPIONEER S1™ Stimulator/Generator for the Treatment of Hypertension
Sympathetic Mapping/Ablation of Renal Nerves Trial
(SMART Study)
CFDA Registration Trial/13 Hospital/220 Patients
Started to Enroll Patients in November, 2016

8. Purpose of the Study
To evaluate the safety and efficacy of targeted renal sympathetic denervation in patients with uncontrolled、primary hypertension for at least 6 months, then after standardized drug therapy (at least two drugs) for at least 28 days, office BP is still ≥ 150mmHg, ≤180mmHg

9. Enrollment Criteria：
（1）Age≥18 years, ≤65 Year male or female without pregnancy ;
（2）Primary hypertension；
（3）Office SBP≥ 150mmHg, ≤180mmHg；heart rate at rest ≥ 70bpm without β blocker；Resting HR is not considered if β‐blocker is taken;
（4）ASBP measurement ≥135 mmHg;
（5）Hypertension history ≥6m；
（6）Uncontrolled hypertension with 6m anti-hypertension drug therapy; properly consented; standardized medication (at least two drugs) for at least 28 days before enrollment, office BP≥150mmHg， ≤180mmHg；
（7）Consented and willing to accept out-patient follow-up.

10. Study Chart：
Consent
Uncontrolled Hypertension/at least 6 month Medication, SBP≥150mmHg, ≤180mmHg
Lab Tests
Running in：standard medication for at least 28 days （at least two drugs）
After 28 days of standard medication, Office BP still ≥150mmHg，≤180mmHg，patients are enrolled
Lab Tests
Renal Angiography
1:1Randomization

11. Assessment of procedure safety Post-Procedure Office BP/24 hour AMBP
1:1Randomlization
Renal Ablation
N =110
Sham
N =110
Assessment of procedure safety
Post-Procedure Office BP/24 hour AMBP
Within 3 months after the procedure, if SBP mmHg , there are no changes in medication , unless:
SBP＞160mmHg，increase the drug dose or class according to a strict regimen;
SBP＜120mmHg，decrease the drug dose or class according to a strict regimen；
Or SBP＜130mmHg，decrease the drug dose or class according to a strict regimen due to patients showed difficulties to tolerate the drugs.

12. Three months after the procedure：
SBP<120mmmHg，reduce anti-hypertension drugs；
SBP<140mmmHg，no changes in drug regimen；
Uncontrolled SBP，medication changes according to a strict drug regimen
Follow-up：
Office BP and urine sample 7days, 1m, 2m, 3m, 4m, 5m, 6m, 9m and 12m after the procedure.
CTA and 24-hour ambulatory BP
The changes in medications are determined by follow-up physicians ;
Follow-up physicians and procedure performance physicians are blind each other;
Drug adherence is monitored by HPLC- MS/MS (urine samples);
The study will be performed at 16 hospitals.

13. Primary Efficacy Endpoints
The Control Rate of Office SBP ( SBP<140mmHg) at 6 month after the treatment
The composite index of anti-hypertension drugs at 6 months after the treatments
Composite Index based on the class numbers and doses of medications:
Composite Index = Weights X ( sum of doses)
# Classes: Weights;
Dose: Factors
One Standard Dose is defined as 1; Half dose: 0.5，Double Dose: 2 , et al
Examples:
Two classes of drugs were taken，double doses were used for one class and half dose was used for another class: The Index = 2*（2+0.5）=5 ；
Five classes of drugs were taken ，one standard dose was used for each class, respectively, The Index = 5*（ ）=25
Weights
1 Class 1
2 Classes 2
3 Classes 3
4 Classes 4
5 Classes 5

14. Secondary Efficacy Endpoints:
The Change in mean 24-hour Ambulatory Systolic Blood Pressure Measurement at month 6
The change in mean 24 hour Ambulatory Systolic, Diastolic and Mean Arterial Pressure at 24 hours after the treatment
Office BP at 1m、2m、3m、4m、5m、6m、9m、12 m after the treatment；
The composite index of anti-hypertension drugs at 1m、2 m 、3m、4m、5m、9m、12m after the treatment

15. Safety Endpoints
MASE
Cardiac function
Renal function

16. Standardization of Anti-hypertension Drug Regimen
Standardized Drugs, Doses and Manufacture：
Class
Name
Commercial Name
Manufacture
Standard Dose
Maximum Dose 1
ARB
Irbesartan
Aprovel/
安博维
Sannofi（Hanzhou, China）
150mg/Day
300mg/Day 2
CCB
Amlodipine
Norvasc/
络活喜
Pfizer（Dalian, China）
5mg/Day
10mg/Day 3
Β Receptor Blocker
Metoprolol Sustained Release
Betaloc Zok/倍他乐克
缓释片
AstraZeneca
47.5mg/Day
95mg/Day 4
Diuretic
Hydrochlorothiazide
氢氯噻嗪片
Changzhou Pharmaceutical
25mg/Day
50mg/Day 5
α Receptor Blocker
Terazosin Hydrochloride
高特灵
Abbott (Shanghai)
2mg/Day
4mg/Day 6
Combination Drug
Irbesartan+
Coaprovel/
安博诺
Sanofi（Hanzhou, China）
Irbesartan 150mg+
Hydrochlo. 12.5mg/Day
Irbesartan 300mg+Hydrochlo 25mg/Day

17. Running In Period
The first visit: SBP≥150mmHg，≤180mmHg： A．Patient with one drug：need add another class drug，ARB is the first choice. If CCB is taken, ARB will be added; if ARB is taken, CCB will be added; if other class of drug is taken this drug must be replaced by the same class of drug and add ARB. B．Patient with two drugs: these two drugs need to be replaced by drugs/doses in the Regimen. In the case patient still has severe complains and diuretic is not taken, diuretic or Coaprovel is added. C．Patients with three drugs: these three drugs are switched to the same classes of drugs in the list of Standardization of Drug Regimen with defined doses. D．Patient with combined drug: it should switch to Coaprovel; If BP is still uncontrolled and patient has severe complains, CCB will be added. E. If ACEI is used , it needs to replaced by ARB. F. The standardized anti-hypertension drug therapy much be performed for at least 28 days.

18. A Strict Regimen for Post-randomization
Medication Changes
Regimen to Add Drugs：Increase in dosing is firstly selected until defined maximum dose; if systolic BP is still not controlled, then another class drug is added according to the order as above . If the class of drug is not proper to the patient evidenced by clinical signs the class can be escaped and next class of drug is used. For instance, patient with irbesartan 50mg/day + Amlodipine 5mg/day，SBP is still >160mmHg. HR is < 65 b/min，Metoprolol will be escaped and hydrochlorothiazide is used。
Regimen to Reduce Drugs: Decrease in dosing is considered firstly; if it is needed then the class of drug is reduced according to above order。
Order to Add Drugs
Irbesartan
Amlodipine
Metoprolol
Hydro-chlorothiazide
Terzzosin
Hydrochloride
Order to Reduce Drugs

19. Renal Sympathetic Mapping/Ablation
Right
Left
Before Mapping/Ablation
During Mapping/Ablation
After Mapping/Ablation

20. Preliminary Data N=4 Left Renal A. Right Renal A. Total Mapping 23 26
Left Renal A.
Right Renal A.
Total
Mapping 23 26 49
Average
5.75
6.5
Hot Sites
 13
 16
29 
3.25 4 % 57 62 59
2nd Ablation 5 7 12 39 43 41

21. Changes in BP in Responses to Renal Stimulations
The Responses of Blood Pressure to Renal Stimulation Before Renal Ablation
SBP
(mmHg)
Before
After
△SBP
DBP
△DBP
MAP
△MAP
Mean
160
179 19 86 95 9
111
122 11 SE
4.0
4.9
2.2
3.7
3.8
1.1
2.4
2.6
1.2
The Responses of Blood Pressure to Renal Stimulation After Renal Ablation
Effective Ablation：26/29=90%
△DBP (mmHg)
△MAP(mmHg)
162
167 5 89 90 3
110
116
4.6
4.7
1.9
3.9
4.1
1.0
0.9

22. Preliminary Data 28 Days of Standard Drug Therapy
Time
Office BP mmHg
Heart Rate b/min
09:09:53
156/108
102
09:11:53
155/101
104
09:13:21
165/105
103
Mean
162/103
24 Hour AMBP：
Systolic： Max184mmHg Min137 mmHg Mean 161mmHg
Diastolic：Max 123mmHg Min 049mmHg Mean 097mmHg
5 Days after the Procedure
Time
Office BP mmHg
Heart Rate b/min
13:52:33
145/097 91
13:53:38
145/096 92
13:54:51
140/079 90
Mean
143/091
24 Hour AMBP：
Systolic： Max 216mmHg  Min112 mmHg  Mean 147mmHg
Diastolic：Max 158mmHg  Min 57mmHg  Mean 99mmHg

23. Preliminary Data One Month after the Procedure
Time
Office BP mmHg
Heart Rate b/min
09:01:19
144/102 NA
09:02:35
142/97
09:03:42
138/90
Mean
141/96
105
Two Months after the Procedure
Time
Office BP mmHg
Heart Rate b/min
09:08:29
125/88 NA
09:09:35
134/88
09:10:43
140/89
Mean
133/88
104

24. Summary Targeted Renal Sympathetic Denervation
Proper Patient Population
Not intend to “bit” drug therapy; as an alternative therapy to address issues of drug therapy
Waiting for more results

25. Thank You