1. A Prospective, Multicenter, Randomized trial to Assess Efficacy and Safety of the CERA Occluder in Congenital Heart Disease (ASD/VSD/PDA): CERA TRIAL
Zhi-wei Zhang MD On Behalf Of Cera Trail Investigators Professor Of Guangdong General Hospital

2. Background
Heartr occluder
Cera occluder
HeartrTM occluder is a self-expandable, double disc device made from a Nitinol wire mesh.
CeraTM occluder (ASD, VSD, PDA) developed from the prior generation occluder (ASD, VSD, PDA)- HeartrTM occluder.
In order to decrease the dissolution of nickel ion, the surface of nitinol wire was covered with TiN membrane

3. Background
Cera occluder
Heartr occluder
The results of animals showed that the CERA occluder reduce inflammation and thrombus, promote the endothelial cells growth

4. Objective
To Establish The Safety And Effectiveness Of Cera TM Occluder (ASD/ VSD/ PDA) Compared With HeartrTMOccluder In A Multicenter, Randomized Clinical Trial .

5. Study design CeraTM Occluder n=232 (ASD/VSD/PDA)
Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study 464 patients at 11 centers
CeraTM Occluder n=232 (ASD/VSD/PDA)
Heartr TM occluder n=232 (ASD/VSD/PDA)
Clinical follow-up
(ECHO/ ECG /X-RAY)
30 d
3 mo
6 mo
11 Sites In China

6. Major inclusion and exclusion criteria (ASD)
Echocardiographic evidence of ostium secundum atrial septal defect
Age ≥2 years and ≤ 65 years
The maximum stretch diameter of the defect shorter than 40 mm, and total length of the atrial septal longer than the device
The margins of the defect are larger than 5mm to the coronary sinus, AV valves or right upper lobe pulmonary vein.
The ostium primum ASD or coronary sinus ASD
Severe pulmonary hypertension and right to left shunt
Severe myocardial diseases or valve diseases independent with ASD
Thrombus in cardiac cavity or vein absolutely closured by lower limb venous thrombosis

7. Major inclusion and exclusion criteria (VSD)
Echocardiographic evidence of Ventricular Septum Defect (VSD)
age ≥3 years and ≤65 years.
diameter of left ventricular ranged at 3-14 mm (children < 10 mm). if the right perimembrane VSD is multiple, one of these holes should larger than 2 mm at least
the margins of the defect are larger than 2 mm to the aortic valve without observed aortic valve prolapsed and reflux
Left to right shunt of ventricular shunt in main
Aortic valve prolapsed, aortic insufficiency, or have a poor anatomy position of the VSD where interfere the function of aortic valve or atrioventricular valve
Severe pulmonary hypertension and right to left shunt
Absolutely closured by lower limb venous thrombosis

8. Major inclusion and exclusion criteria (PDA)
Echocardiographic evidence of patent ductus arteriosus defect (PDA)
Single PDA, or have PDA and other slight cardiovascular abnormalities without surgery therapy
Age ≥4 months, ≤65 years
Weight ≥6 kg
The minimum diameter of the PDA ranged at 2-16 mm
Other cardiac anomalies should corrected by surgery therapy, or cardiac anomaly depend on the presence of PDA
Severe pulmonary hypertension and right to left shunt

9. Study Endpoint Primary Study Endpoint Secondary Study Endpoint
Procedure success through 6 months post-randomization
Secondary Study Endpoint
Adverse events (AEs) directly related to the device, procedure in 6 months

10. Outcome definitions Procedure success: Adverse events (aes)
Position of the occluder is proper by TTE/TEE observing, and with litter or without residual shunt and without observed atrioventricular valve reflux.
Adverse events (aes)
Hemolysis: any drop in haemoglobin (hb) of >2.5 g/dl within 24 hours
Severe acute haemolysis: hb ≤5 g/dl or received blood transfusion according to clinical judgement of study physician.
Thromboembolism: thrombosis that required thrombolytic therapy
Migration or shedding of the occlude: required surgical removal of the device

11. Follow up Clinical and chest x-ray, ECG, echocardiogram follow
1, 3, 6 months post-randomization

12. CERA Trial – participants
“11 centers in china”
Investigator
HOSPITAL N 1
Zhang zhiwei
Guangdong General Hospital,
136 2
Zhou shenghua
Second Xiangya Hospital, Central South University, 84 3
Zhou daxin
Zhongshan Hospital Fudan University, 40 4
Pu xiaoqun
Xiangya Hospital Central-south University 5
Yu bo
The 2nd Affiliated Hospital Of Harbin Medical University 6
Ma chunye
The First Hospital Of Jilin University 36 7
Dai zhengxue
Xijing Hospital, The Fourth Military Medical University,, 32 8
Li shumei
The Second Hospital Of Jilin University , 20 9
Chen lianglong
Fujian Medical University Union Hospital 10
Hua yimin
West China Second University Hospital 11
Wu feifeng
The First Affiliated Hospital Of Guangxi Medical University,

13. Sample size calculation and statistical analysis
Statistical assumptions
One-sided 95% upper confidence bound for the difference in means between groups
Margin of difference to support non-inferiority was 0.10
Alpha=0.05, Power=80%
A sample size of 464 patients(232 patients per groups ) was calculated
All enrolled patients were included in the analyses of primary and secondary outcomes according to the intention-to-treat principle

14. Clinical trial organization
Principal Investigators: Zhiwei Zhang , MD
Guangdong General Hospital
Clinical Events Committee Bo Yu, MD
The 2nd Affiliated Hospital Of Harbin Medical University
Data Safety Monitoring Board: Shenghua Zhou, MD
Second Xiangya Hospital, Central South University,
Data Management : Hao Yu , PHD
Nanjing Medical University

15. Patient population CERA HEARTR P-VALUE Total Patients Enrolled 232
Intent To Treat 1 3
Anatomical Condition 2
Shunt Minor
Total Attempted Patients
231
229

16. patients demographics
CERA(n=231)
HEARTR (n=229)
P-VALUE
Age (years)
TOTAL
19.7±17.0 (0.4～68.0)
20.8±17.0 (0.2～61.0)
0.31
ASD
28.9±15.8
31.8±15.8
0.25
VSD
12.6±12.5
13.2±11.8
0.41
PDA
17.6±18.1
17.2±16.9
0.82
<20years%
131(56.71%)
133(58.08%)
0.77
22(28.21%)
20(25.97%)
0.75
62(80.52%)
59(77.63%)
0.66
47(61.84%)
54(71.05%)
0.23
Gender male(%)
79(34.20%)
74(32.31%)
0.67
26(33.33%)
19(24.68%)
0.24
36(46.75%)
38(50.00%)
0.69
17(22.37%) NS

17. patients demographics
CERA (n=231)
HEARTR(n=229)
Weight (kg)
TOTAL
37.2±20.5 (6.5～90.0)
40.2±19.9 (6.0～90.0)
0.12
ASD
47.9±16.6
52.8±14.6
0.06
VSD
31.0±19.9
32.2±19.0
0.42
PDA
32.1±20.6
35.2±19.5
0.34
Height (cm)
133.4±33.2(46.0～187.0)
136.7±30.3 (60.0～185.0)
0.48
150.5±23.1
156.4±17.4
0.30
127.0±29.1
125.7±25.5
0.82
121.5±38.5
126.4±34.7
0.40
Heart Murmur(%)
194 (84.0%)
195 (85.2%)
0.73
62 (79.5%)
57 (74.0%)
71 (92.2%)
70 (92.1%) NS
61 (80.3%)
68 (89.5%)
0.11

18. Baseline medical data CERA HEARTR P-VALUE n=231 n=229 CHF 13(5.63%)
18(7.86%)
0.34
Failure To Thrive
2(0.87%) NS
CAD
4(1.75%)
0.21
Diabetes
Embolization
1(0.43%)
0.62
Stroke
Hypertension
9(3.90%)
9(3.93%)
Syncope
3(1.30%)
0(0.00%)
0.25
Chest Ache
4(1.73%)
7(3.06%)
0.38
Major Complications: Events that are life threatening, prolong hospitalization or have long-term
consequences or need for ongoing therapy. These include but are not limited to cerebral embolism,
cardiac perforation with tamponade, endocarditis, pericardial effusion with tamponade, repeat surgery,
death, cardiac arrhythmias requiring permanent pacemaker placement or long term anti-arrhythmic
medication and device embolizations requiring immediate surgical removal.
Minor Complications: Device embolization with percutaneous retrieval, cardiac arrhythmia with treatment,
phrenic nerve injury, hematoma, other vascular access site complications, retroperitoneal hematoma,
surgical wound complications, other procedural complications, pericardial effusion requiring medical
management, evidence of device associated thrombus formation without embolization (with or without
treatment) and marker band embolization without known sequelae.

19. Baseline echocardiographic characteristics
CERA
HEARTR
P-VALUE
ASD
N=78
N=77
Defect size (mm)
16.8±6.2 (6.0～30.0 )
19.5±6.2 (5.5～35.0)
0.01
LVEED
38.6±6.6
39.025±6.025
0.71
RVD
34.8±11.7
36.499±12.149
0.42
RAD
40.4±9.4
42.300±10.993
0.33
LVEF
66.6±5.6
66.520±6.940
0.84
VSD
N=76
6.0±2.6 ( )
5.8±2.5 ( )
0.64 LV
39.3±7.5
40.5±7.7
0.34
LAD
26.8±6.6
27.2±6.7
0.92
66.6±6.1
68.7±7.9
0.09
PDA
5.5±2.2 (2.1～10.4)
5.9±2.8 (2.6～16.0 )
0.58
46.6±12.1
48.4±12.4
0.53
29.9±8.4
31.5±8.2
0.24 EF
65.5±7.2
65.7±8.0
0.93

20. Baseline characteristics
CERA
HEARTR
P-VALUE
Qp/QS
ASD (CERA N=48, HEARTR N=47)
2.24±0.88
2.62±1.66
0.49
VSD (CERA N=59, HEARTR N=56)
1.53±0.84
1.53±0.54
0.38
PDA (CERA N=31, HEARTR N=35)
4.31±6.11
3.31±4.19
0.70
PAP(M)
ASD (CERA N=63, HEARTR N=62)
20.13±8.38
19.60±5.25
0.88
VSD (CERA N=65, HEARTR N=64)
16.09±5.68
17.39±6.34
0.29
PDA (CERA N=64, HEARTR N=62)
25.25±13.49
25.66±13.97
0.93
PAP/AP
ASD (CERA N=57, HEARTR N=55)
0.27±0.10
0.26±0.07
0.83
VSD (CERA N=56, HEARTR N=57)
0.24±0.07
0.25±0.07
0.56
PDA (CERA N=63, HEARTR N=59)
0.35±0.15
0.33±0.15
0.39
Major Complications: Events that are life threatening, prolong hospitalization or have long-term
consequences or need for ongoing therapy. These include but are not limited to cerebral embolism,
cardiac perforation with tamponade, endocarditis, pericardial effusion with tamponade, repeat surgery,
death, cardiac arrhythmias requiring permanent pacemaker placement or long term anti-arrhythmic
medication and device embolizations requiring immediate surgical removal.
Minor Complications: Device embolization with percutaneous retrieval, cardiac arrhythmia with treatment,
phrenic nerve injury, hematoma, other vascular access site complications, retroperitoneal hematoma,
surgical wound complications, other procedural complications, pericardial effusion requiring medical
management, evidence of device associated thrombus formation without embolization (with or without
treatment) and marker band embolization without known sequelae.

21. Clinical utility results
CERA
HEARTR
P-VALUE
ASD
Procedure time (min)
58.2±33.5
58.0±25.5
0.86
Range (min)
20.0～270.0
20.0～130.0
Occluder waist size (mm)
24.2±7.8
27.3±8.5
0.02
Range (mm)
10.0～40.0
10.0～42.0
VSD
74.5±30.4
77.5±28.4
0.47
20.0～180.0
30.0～155.0
7.8±2.9
8.0±2.6
0.25
4.0～18.0
PDA
59.8±19.3
53.5±21.7
0.03
25.0～120.0
9.0±3.0
9.3±4.5
0.79
4.0～14.0
4.0～26.0

22. Technical and procedure success
CERA
HEARTR
P-VALUE
Technical Success
228/231(98.70%)
227/229 (99.13%) NS
ASD
76/78 (97.44%)
77/77 (100.00%)
0.50
VSD
76/77 (98.70%)
74/76 (97.37%)
0.62
PDA
76/76 (100.00%)
procedure success
226/228(99.12%)
225/227(99.12%)
1.0000
75/76 (98.68%)
73/74 (98.65%)
Major Complications: Events that are life threatening, prolong hospitalization or have long-term
consequences or need for ongoing therapy. These include but are not limited to cerebral embolism,
cardiac perforation with tamponade, endocarditis, pericardial effusion with tamponade, repeat surgery,
death, cardiac arrhythmias requiring permanent pacemaker placement or long term anti-arrhythmic
medication and device embolizations requiring immediate surgical removal.
Minor Complications: Device embolization with percutaneous retrieval, cardiac arrhythmia with treatment,
phrenic nerve injury, hematoma, other vascular access site complications, retroperitoneal hematoma,
surgical wound complications, other procedural complications, pericardial effusion requiring medical
management, evidence of device associated thrombus formation without embolization (with or without
treatment) and marker band embolization without known sequelae.
Technical Success: successful deployment of the device,
Patients who received the device procedure who had successful closure of the defect(≤2.0mm residual shunt )

23. Closure success CERA HEARTR P-VALUE 1MONTH 220/224 (98.21%)
TATOL
220/224 (98.21%)
217/224 (96.88%)
0.54
ASD
71/74 (95.95%)
72/75 (96.00%) NS
VSD
73/74 (98.65%)
69/73 (94.52%)
0.21
PDA
76/76(100.00%)
3 MONTH
211/216 (97.69%)
210/217 (96.77%)
0.56
68/71 (95.77%)
70/74 (94.59%)
71/72 (98.61%)
0.37
72/73 (98.63%)
72/72 (100.00%)
6MONTH
222/224 (99.11%)
213/218 (97.71%)
0.28
74/76 (97.37%)
77/77 (100.00%)
0.05
71/71 (100.00%)
Major Complications: Events that are life threatening, prolong hospitalization or have long-term
consequences or need for ongoing therapy. These include but are not limited to cerebral embolism,
cardiac perforation with tamponade, endocarditis, pericardial effusion with tamponade, repeat surgery,
death, cardiac arrhythmias requiring permanent pacemaker placement or long term anti-arrhythmic
medication and device embolizations requiring immediate surgical removal.
Minor Complications: Device embolization with percutaneous retrieval, cardiac arrhythmia with treatment,
phrenic nerve injury, hematoma, other vascular access site complications, retroperitoneal hematoma,
surgical wound complications, other procedural complications, pericardial effusion requiring medical
management, evidence of device associated thrombus formation without embolization (with or without
treatment) and marker band embolization without known sequelae.
Closure success :among patients that were technical successes, closure of the defect (ASD/VSD/PDA defined as a shunt ≤2mm) without the need for surgical repair significant

24. Nickel serum concentrations —paediatric patients in Guangdong General Hospital
Time
CERA (ng/ml)
HEARTR (ng/ml)
P-VALUE
Before
0.827±0.665（n=46）
0.586±0.518 （n=47）
0.054
24-hours
0.654±0.444 （n=45）
0.974±0.512 （n=45） ﹡
0.002
1 month
0.937±0.495 （n=45）
1.982±0.694（n=40） ﹡﹟
0.000
3 months
0.824±0.468 （n=39）
1.401±0.918 （n=42）﹡﹟
0.001
6 months
0.486±0.176（n=43）
0.617±0.421 （n=43）☆＆
0.065

25. Nickel serum concentrations
The rise in the mean serum levels of nickel 24 hours and 1 and 3 months after implantation was significant in the control group (P<0.005), but no significant difference in the CERA group.
There was no significant difference in the mean serum levels of nickel before implantation and 6 months after the procedure （P>0.5）.
The mean serum levels of nickel are significant higher of the control group than the CERA group at 24 hours and 1 and 3 months after implantation (P<0.005).

26. Nickel serum concentrations
6 month
3 month
1 month
24 hours
Before
2.10
1.80
1.50
1.20
0.90
0.60
0.30
Nickel concentration (ng/ml） B
A CERA
B HEARTR

27. Results cera heartr Major complications
Cardiac Arrhythmia Requiring Major Treatment
Death (Device Or Procedure )
Device Embolization with percutaneous removal
device Embolization With Surgical Removal
Pericardial Effusion with tamponade
Device Dislocation With Surgical Removal 1

28. Results minor complications cera heartr P-VALUE Anemia
Allergic Reaction (Drug)
Cardiac Arrhythmia Minor Treatment
16(6.93)
25(10.92)
0.13
ASD
2(2.56)
5(6.49)
0.28
VSD
11(14.29)
19(25.00)
0.10
PDA
3(3.95)
1(1.32)
0.62
Thrombus Formation
Upper Respiratory Infection 2
Headaches/Possible TIA
Pericardial Effusion
Pseudoaneurysm
Puncture Site Hematoma
Venous Thrombosis 1

29. Conclusion
animal experiments and in vitro experiments both show that ceramic membrane occluder can restrain the thrombosis and promote the growth of endothelial tissue.
This trial show the ceramic occluder occluder (CERATM) have the same clinical safety and effectiveness, compare with the general Nitinol occluder (heartrTM ).

30. Conclusion
according to this clinical trail , there is no statistical significance between the CERA group and HEARTR group .
But we believe that for this difference was not significant due mainly to the design of this study and test methodology, may need a larger sample size and longer observation time to identify the Obvious advantage of the ceramic membrane occluder relative to the normal occluder .

31. Thanks