Zhi-wei Zhang MD On Behalf Of Cera Trail Investigators Professor Of Guangdong General Hospital A Prospective, Multicenter, Randomized trial to Assess Efficacy

Zhi-wei Zhang MDZhi-wei Zhang MDOn Behalf Of Cera Trail InvestigatorsOn Behalf Of Cera Trail Investigators

Professor Of Guangdong General HospitalProfessor Of Guangdong General Hospital

A Prospective, Multicenter, Randomized trial A Prospective, Multicenter, Randomized trial to Assess Efficacy and Safety of the CERA to Assess Efficacy and Safety of the CERA

Occluder in Congenital Heart Disease Occluder in Congenital Heart Disease

(ASD/VSD/PDA):(ASD/VSD/PDA): CERA TRIALCERA TRIAL

BackgroundBackground

HeartrHeartrTMTM occluder is a self-expandable, double disc device made occluder is a self-expandable, double disc device made from a Nitinol wire mesh.from a Nitinol wire mesh.

CeraCeraTMTM occluder (ASD, VSD, PDA) developed from the prior occluder (ASD, VSD, PDA) developed from the prior generation occluder (ASD, VSD, PDA)- Heartrgeneration occluder (ASD, VSD, PDA)- HeartrTM TM occluder.occluder.

In order to decrease the dissolution of nickel ion, the surface of In order to decrease the dissolution of nickel ion, the surface of nitinol wire was covered with TiN membrane nitinol wire was covered with TiN membrane

Heartr occluder Cera occluder

BackgroundBackground

Heartr occluder Cera occluder

• The results of animals showed that the CERA occluder The results of animals showed that the CERA occluder

reduce inflammation and thrombus, promote the reduce inflammation and thrombus, promote the

endothelial cells growthendothelial cells growth

ObjectiveObjective To Establish The Safety And Effectiveness Of To Establish The Safety And Effectiveness Of

Cera Cera TMTM Occluder (ASD/ VSD/ PDA) Compared Occluder (ASD/ VSD/ PDA) Compared

With HeartrWith HeartrTMTMOccluder In A Multicenter, Occluder In A Multicenter,

Randomized Clinical Trial .Randomized Clinical Trial .

Study designStudy design

Randomized, Open Label, Active Control, Parallel Assignment, , Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study 464 patients at 11 centersSafety/Efficacy Study 464 patients at 11 centers

CeraTM Occluder n=232 (ASD/VSD/PDA)

Heartr TM occluder n=232 (ASD/VSD/PDA)

30 d 3 mo 6 mo

Clinical follow-up

(ECHO/ ECG /X-RAY)

11 Sites In China

Major inclusion and exclusion Major inclusion and exclusion criteria (ASD)criteria (ASD)

Echocardiographic evidence of ostium secundum atrial septal defect

Age ≥2 years and ≤ 65 years Age ≥2 years and ≤ 65 years The maximum stretch The maximum stretch

diameter of the defect diameter of the defect shorter than 40 mm, and shorter than 40 mm, and total length of the atrial total length of the atrial septal longer than the deviceseptal longer than the device

The margins of the defect The margins of the defect are larger than 5mm to the are larger than 5mm to the coronary sinus, AV valves or coronary sinus, AV valves or right upper lobe pulmonary right upper lobe pulmonary vein.vein.

The ostium primum ASD or The ostium primum ASD or coronary sinus ASDcoronary sinus ASD

Severe pulmonary Severe pulmonary hypertension and right to hypertension and right to left shuntleft shunt

Severe myocardial diseases Severe myocardial diseases or valve diseases or valve diseases independent with ASDindependent with ASD

Thrombus in cardiac cavity Thrombus in cardiac cavity or vein absolutely closured or vein absolutely closured by lower limb venous by lower limb venous thrombosisthrombosis

inclusion exclusion

Major inclusion and exclusion Major inclusion and exclusion criteria (VSD)criteria (VSD)

Echocardiographic evidence of Ventricular Ventricular Septum Defect (VSD) Septum Defect (VSD)

age ≥3 years and ≤65 age ≥3 years and ≤65 years.years.

diameter of left ventricular diameter of left ventricular ranged at 3-14 mm ranged at 3-14 mm (children < 10 mm). if the (children < 10 mm). if the right perimembrane VSD is right perimembrane VSD is multiple, one of these multiple, one of these holes should larger than 2 holes should larger than 2 mm at leastmm at least

the margins of the defect the margins of the defect are larger than 2 mm to are larger than 2 mm to the aortic valve without the aortic valve without observed aortic valve observed aortic valve prolapsed and refluxprolapsed and reflux

Left to right shunt of Left to right shunt of ventricular shunt in mainventricular shunt in main

Aortic valve prolapsed, Aortic valve prolapsed, aortic insufficiency, or have aortic insufficiency, or have a poor anatomy position of a poor anatomy position of the VSD where interfere the the VSD where interfere the function of aortic valve or function of aortic valve or atrioventricular valve atrioventricular valve


Absolutely closured by Absolutely closured by lower limb venous lower limb venous thrombosisthrombosis

inclusion exclusion

Major inclusion and exclusion Major inclusion and exclusion criteria (PDA)criteria (PDA)

Echocardiographic evidence of patent ductus arteriosus patent ductus arteriosus defect (PDA) defect (PDA)

Single PDA, or have PDA Single PDA, or have PDA and other slight and other slight cardiovascular cardiovascular abnormalities without abnormalities without surgery therapysurgery therapy

Age ≥4 months, ≤65 yearsAge ≥4 months, ≤65 years Weight ≥6 kgWeight ≥6 kg The minimum diameter of The minimum diameter of

the PDA ranged at 2-16 mmthe PDA ranged at 2-16 mm

Other cardiac anomalies Other cardiac anomalies should corrected by surgery should corrected by surgery therapy, or cardiac anomaly therapy, or cardiac anomaly depend on the presence of depend on the presence of PDAPDA


inclusion exclusion

Study Endpoint Study Endpoint

Primary Study EndpointPrimary Study Endpoint Procedure success through 6 months post-Procedure success through 6 months post-

randomization randomization

Secondary Study EndpointSecondary Study Endpoint Adverse events (AEs) directly related to the Adverse events (AEs) directly related to the

device, procedure in 6 months device, procedure in 6 months

Outcome definitions Outcome definitions Procedure success:Procedure success:

Position of the occluder is proper by TTE/TEE observing, and Position of the occluder is proper by TTE/TEE observing, and with litter or without residual shunt and without observed with litter or without residual shunt and without observed atrioventricular valve reflux.atrioventricular valve reflux.

Adverse events (aes)Adverse events (aes) Hemolysis:Hemolysis: any drop in haemoglobin (hb) of >2.5 g/dl within any drop in haemoglobin (hb) of >2.5 g/dl within

24 hours 24 hours Severe acute haemolysis: hb ≤5 g/dl or received blood Severe acute haemolysis: hb ≤5 g/dl or received blood

transfusion according to clinical judgement of study transfusion according to clinical judgement of study physician.physician.

Thromboembolism: thrombosis that required thrombolytic Thromboembolism: thrombosis that required thrombolytic therapytherapy

Migration or shedding of the occlude: required surgical Migration or shedding of the occlude: required surgical removal of the deviceremoval of the device

Follow upFollow up

Clinical and chest x-ray, ECG, Clinical and chest x-ray, ECG,

echocardiogram followechocardiogram follow

1, 3, 6 months post-randomization 1, 3, 6 months post-randomization

CERA Trial – participantsCERA Trial – participants

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 40

5 Yu bo The 2nd Affiliated Hospital Of Harbin Medical University 40

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 20

10 Hua yimin West China Second University Hospital 8

11 Wu feifeng The First Affiliated Hospital Of Guangxi Medical University, 8

“11 centers in china”

Sample size calculation and statistical Sample size calculation and statistical analysisanalysis

Statistical assumptionsStatistical assumptions One-sided 95% upper confidence bound for the difference in One-sided 95% upper confidence bound for the difference in

means between groups means between groups Margin of difference to support non-inferiority was 0.10Margin of difference to support non-inferiority was 0.10 Alpha=0.05, Power=80%Alpha=0.05, Power=80%

A sample size of 464 patients(232 patients per groups A sample size of 464 patients(232 patients per groups ) was calculated) was calculated

All enrolled patients were included in the analyses of All enrolled patients were included in the analyses of primary and secondary outcomes according to the primary and secondary outcomes according to the intention-to-treat principleintention-to-treat principle

Clinical trial organization Clinical trial organization

Principal Investigators:Principal Investigators: Zhiwei Zhang , MD Zhiwei Zhang , MD

Guangdong General HospitalGuangdong General Hospital

Clinical Events CommitteeClinical Events Committee Bo Yu, MD Bo Yu, MD

The 2nd Affiliated Hospital Of Harbin Medical University The 2nd Affiliated Hospital Of Harbin Medical University

Data Safety Monitoring Board:Data Safety Monitoring Board: Shenghua Zhou, MD Shenghua Zhou, MD

Second Xiangya Hospital, Central South University, Second Xiangya Hospital, Central South University,

Data Management :Data Management : Hao Yu , PHD Hao Yu , PHD

Nanjing Medical University Nanjing Medical University

Patient population Patient population

CERACERA HEARTRHEARTR P-VALUEP-VALUE

Total Patients Enrolled 232 232

Intent To Treat 1 3

Anatomical Condition 1 2

Shunt Minor 0 1

Total Attempted Patients 231 229

patients demographicspatients demographicsCERA(n=231) HEARTR (n=229) P-VALUEP-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%

TOTAL 131(56.71%) 133(58.08%) 0.77

ASD 22(28.21%) 20(25.97%) 0.75

VSD 62(80.52%) 59(77.63%) 0.66

PDA 47(61.84%) 54(71.05%) 0.23

Gender male(%)

TOTAL 79(34.20%) 74(32.31%) 0.67

ASD 26(33.33%) 19(24.68%) 0.24

VSD 36(46.75%) 38(50.00%) 0.69

PDA 17(22.37%) 17(22.37%) NS

patients demographicspatients demographicsCERA (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)TOTAL 133.4±33.2(46.0 ～ 187.0) 136.7±30.3 (60.0 ～ 185.0) 0.48

ASD 150.5±23.1 156.4±17.4 0.30

VSD 127.0±29.1 125.7±25.5 0.82

PDA 121.5±38.5 126.4±34.7 0.40

Heart Murmur(%)

TOTAL 194 (84.0%) 195 (85.2%) 0.73

ASD 62 (79.5%) 57 (74.0%) 0.42

VSD 71 (92.2%) 70 (92.1%) NS

PDA 61 (80.3%) 68 (89.5%) 0.11

Baseline medical dataBaseline medical data

CERA HEARTR P-VALUE

n=231 n=229CHF 13(5.63%) 18(7.86%) 0.34

Failure To Thrive 2(0.87%) 2(0.87%) NS

CAD 2(0.87%) 4(1.75%) 0.21

Diabetes 2(0.87%) 2(0.87%) NS

Embolization 1(0.43%) 2(0.87%) 0.62

Stroke 1(0.43%) 2(0.87%) 0.62

Hypertension 9(3.90%) 9(3.93%) NS

Syncope 3(1.30%) 0(0.00%) 0.25

Chest Ache 4(1.73%) 7(3.06%) 0.38

Baseline echocardiographic Baseline echocardiographic characteristicscharacteristics

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=77 N=76

Defect size (mm) 6.0±2.6 (2.0-13.0) 5.8±2.5 (2.3-14.0) 0.64

LV 39.3±7.5 40.5±7.7 0.34

LAD 26.8±6.6 27.2±6.7 0.92

LVEF 66.6±6.1 68.7±7.9 0.09

PDA N=76 N=76

Defect size (mm) 5.5±2.2 (2.1 ～ 10.4) 5.9±2.8 (2.6 ～ 16.0 ) 0.58

LV 46.6±12.1 48.4±12.4 0.53

LAD 29.9±8.4 31.5±8.2 0.24

EF 65.5±7.2 65.7±8.0 0.93

Baseline characteristicsBaseline 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)




PAP/AP




Clinical utility resultsClinical utility resultsCERACERA HEARTRHEARTR P-VALUEP-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


Range (min) 20.0 ～ 180.0 30.0 ～ 155.0


Range (mm) 4.0 ～ 18.0 4.0 ～ 18.0

PDA


Range (min) 25.0 ～ 120.0 20.0 ～ 180.0


Range (mm) 4.0 ～ 14.0 4.0 ～ 26.0

Technical and procedure successprocedure success

Technical Success: successful deployment of the device,

Patients who received the device procedure who had successful closure of the defect(≤2.0mm residual shunt )

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%) 76/76 (100.00%) NS

procedure success 226/228(99.12%) 225/227(99.12%) 1.0000

ASD 76/76 (100.00%) 77/77 (100.00%) NS

VSD 75/76 (98.68%) 73/74 (98.65%) NS

PDA 75/76 (98.68%) 75/76 (98.68%) NS

Closure successClosure success

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

CERA HEARTR P-VALUE

1MONTH

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%) 76/76(100.00%) NS

3 MONTH

TATOL 211/216 (97.69%) 210/217 (96.77%) 0.56

ASD 68/71 (95.77%) 70/74 (94.59%) NS

VSD 71/72 (98.61%) 68/71 (95.77%) 0.37

PDA 72/73 (98.63%) 72/72 (100.00%) NS

6MONTH

TATOL 222/224 (99.11%) 213/218 (97.71%) 0.28

ASD 74/76 (97.37%) 73/74 (98.65%) NS

VSD 77/77 (100.00%) 69/73 (94.52%) 0.05

PDA 71/71 (100.00%) 71/71 (100.00%) NS

Nickel serum concentrationsNickel serum concentrations—paediatric patients in Guangdong General Hospital—paediatric patients in Guangdong General Hospital

TimeTime CERA (ng/ml)CERA (ng/ml) HEARTR (ng/ml)HEARTR (ng/ml) PP-VALUE-VALUE

BeforeBefore 0.827±0.6650.827±0.665 （（ n=4n=4

66 ））0.586±0.518 0.586±0.518

（（ n=47n=47 ））0.0540.054

24-hours24-hours 0.654±0.444 0.654±0.444

（（ n=45n=45 ））0.974±0.512 0.974±0.512

（（ n=45n=45 ）） ﹡﹡0.0020.002

1 month1 month 0.937±0.495 0.937±0.495

（（ n=45n=45 ））1.982±0.6941.982±0.694 （（ n=4n=4

00 ）） ﹡﹟﹡﹟0.0000.000

3 months3 months 0.824±0.468 0.824±0.468

（（ n=39n=39 ））1.401±0.918 1.401±0.918

（（ n=42n=42 ））﹡﹟﹡﹟0.0010.001

6 months6 months 0.486±0.1760.486±0.176 （（ n=4n=4

33 ））0.617±0.421 0.617±0.421

（（ n=43n=43 ））☆＆☆＆0.0650.065

Nickel serum concentrationsNickel serum concentrations

The rise in the mean serum levels of nickel 24 The rise in the mean serum levels of nickel 24 hours and 1 and 3 months after implantation hours and 1 and 3 months after implantation was significant in the control group (was significant in the control group (PP<0.005<0.005), but ), but no significant difference in the CERA group.no significant difference in the CERA group.

There was no significant difference in the mean There was no significant difference in the mean serum levels of nickel before implantation and serum levels of nickel before implantation and 6 months after the procedure 6 months after the procedure （（ PP>0.5>0.5 ）） ..

The mean serum levels of nickel are significant The mean serum levels of nickel are significant higher of the control group than the CERA higher of the control group than the CERA group at 24 hours and 1 and 3 months after group at 24 hours and 1 and 3 months after implantation (implantation (PP<0.005<0.005).).

Nickel serum concentrationsNickel serum concentrations

6 month3 month1 month 24 hoursBefore

2.10

1.80

1.50

1.20

0.90

0.60

0.30

Nic

kel

con

cen

trati

on

(n

g/m

l）

B

A CERA B HEARTR

Results Results Major complications Major complications

ceracera heartrheartr

Cardiac Arrhythmia Requiring Major Treatment 0 0

Death (Device Or Procedure ) 0 0

Device Embolization with percutaneous removal 0 0

device Embolization With Surgical Removal 0 0

Pericardial Effusion with tamponade 0 0

Device Dislocation With Surgical Removal 1 0

Results Results minor complicationsminor complications

ceracera heartrheartr P-VALUEP-VALUE

Anemia 0 0

Allergic Reaction (Drug) 0 0

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 0 0

Upper Respiratory Infection 2 0

Headaches/Possible TIA 0 0

Pericardial Effusion 2 0

Pseudoaneurysm 0 2

Puncture Site Hematoma 2 0

Venous Thrombosis 0 1

Conclusion Conclusion animal experiments and in vitro experiments animal experiments and in vitro experiments

both show that ceramic membrane occluder both show that ceramic membrane occluder can restrain the thrombosis and promote the can restrain the thrombosis and promote the growth of endothelial tissue.growth of endothelial tissue.

This trial show the ceramic occluder occluder This trial show the ceramic occluder occluder ((CERACERATMTM) have the same clinical safety and ) have the same clinical safety and effectiveness, compare with the general effectiveness, compare with the general Nitinol occluder (Nitinol occluder (heartrheartrTMTM ). ).

Conclusion Conclusion according to this clinical trail , there is no according to this clinical trail , there is no

statistical significance between the statistical significance between the CERACERA group and group and HEARTRHEARTR group . group .

But we believe that for this difference was not But we believe that for this difference was not significant due mainly to the design of this significant due mainly to the design of this study and test methodology, may need a study and test methodology, may need a larger sample size and longer observation larger sample size and longer observation time to identify the Obvious advantage of the time to identify the Obvious advantage of the ceramic membrane occluder relative to the ceramic membrane occluder relative to the normal occluder .normal occluder .

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Zhi-wei Zhang MD On Behalf Of Cera Trail Investigators Professor Of Guangdong General Hospital A Prospective, Multicenter, Randomized trial to Assess Efficacy