Clinical Trial for Pre-market Registration of Biotronik Qubic Stim Cardiac Stimulator
Phase: NA
Conditions: Arrhythmia
Sponsor: Biotronik (Beijing) Medical Device Ltd.

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Protocol No.: EP034 
 
Clinical Trial Protocol for Pre-market Registration of Biotronik Qubic Stim 
Cardiac Stimulator 
 
Name of Investigational Medical Device: Cardiac Stimulator 
Component and Model of Investigational Medical Device 
Component name 
Model 
Stimulation unit 
Qubic Stim – EP Heart Stimulator 
Control unit 
Qubic Stim – Control Unit 
Patient cable 
PK-128 
Management Category of Investigational Medical Device: 
Class III medical device requiring the clinical trial approval: Yes□  No■ 
Predicate products in China: Yes■  No□ 
Protocol No. and Date: V2.0  2020-4-28 
Clinical Trial Institution: China-Japan Friendship Hospital 
Investigator: Yifeng Zhou 
Sponsor: BIOTRONIK SE & Co.KG 
Agent: BIOTRONIK (Beijing) Medical Device Limited 
 

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Notes: 
1. For multi-center clinical trials, only the leading unit is listed as the clinical trial institution 
on the cover while other institutions are listed in the Protocol. 
2. For multi-center clinical trials, only the coordinating investigator is listed as the 
investigator on the cover. 
3. BIOTRONIK (Beijing) Medical Device Limited is hereinafter referred to as BIOTRONIK. 
 

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Content 
1 Protocol Summary ...................................................................................................... 7 
2 Sponsor Information ................................................................................................... 9 
3 List of All Clinical Trial Institutions and Investigators in Multicenter Clinical 
Trial ............................................................................................................................... 9 
4 Purpose and Content of Clinical Trial ........................................................................ 9 
4.1 Purpose ........................................................................................................................................................ 9 
4.2 Content ....................................................................................................................................................... 10 
5 Background Information of Clinical Trial ............................................................... 10 
6 Product Characteristics, Structure Composition, Operating Principle, Action 
Mechanism of Product and Trial Stretch ..................................................................... 11 
6.1 Product characteristics ................................................................................................................................11 
6.2 Product structure, operating principle and action mechanism ....................................................................11 
6.2.1 System structure and settings ...........................................................................................................11 
6.2.2 Operating principle and action mechanism ..................................................................................... 13 
6.3 Trial stretch ................................................................................................................................................ 13 
7 Indications, Contraindications and Precautions of the Product ............................... 14 
7.1 Indications ................................................................................................................................................. 14 
7.2 Contraindications ....................................................................................................................................... 14 
8 Overall Design .......................................................................................................... 14 
8.1 Trial design ................................................................................................................................................ 14 
8.1.1 Trial objective ................................................................................................................................. 14 
8.1.2 Selection of test method and reasons .............................................................................................. 15 
8.1.3 Measures to reduce and avoid bias ................................................................................................. 15 
8.1.4 Investigational medical device ........................................................................................................ 15 
8.1.5 Subject selection ............................................................................................................................. 15 
8.1.5.1 Inclusion criteria .......................................................................................................................... 15 

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8.1.5.2. Exclusion criteria ........................................................................................................................ 16 
8.1.5.3. Criteria and procedures for termination of trial / trial treatment ................................................. 16 
8.1.5.4. Enrollment time .......................................................................................................................... 17 
8.1.5.5. Expected overall duration of clinical trials and reasons for its determination ............................ 17 
8.1.5.6 Predicted participation duration of each subject .......................................................................... 18 
8.1.5.7 Subject number required in the clinical trial ................................................................................ 18 
8.1.6 Effectiveness evaluation method .................................................................................................... 18 
8.1.6.1 Description of effectiveness parameters ...................................................................................... 18 
8.1.6.2 Methods and time selection for evaluation, record and analysis of effectiveness parameters ..... 18 
8.1.7 Safety evaluation method................................................................................................................ 19 
8.1.7.1 Description of safety parameters ................................................................................................. 19 
8.1.7.2 Method and time selection for valuation, record and analysis of safety parameters .................... 19 
8.1.8 Other concerned data and evaluation indicators ............................................................................. 19 
8.1.8.1 Adverse event ............................................................................................................................... 19 
8.2 Trial flow chart .......................................................................................................................................... 21 
8.2.1 Study follow-up plan ...................................................................................................................... 22 
8.2.2 Device use specification ................................................................................................................. 25 
8.3 Monitoring plan ......................................................................................................................................... 25 
9 Statistical Considerations ......................................................................................... 26 
9.1 Statistical design, methods, and analysis procedures ................................................................................. 26 
9.1.1 Study hypothesis ..................................................................................................................................... 26 
9.1.2 Statistical analysis methods .................................................................................................................... 26 
9.1.3 Statistical analysis procedures ................................................................................................................ 27 
9.2 Calculation of sample size ......................................................................................................................... 27 
9.2.1 Total sample size ..................................................................................................................................... 27 
9.2.2 Case number of each disease in the clinical trial and the determination reasons .................................... 28 
9.2.3 The minimum and maximum subject numbers of each clinical trial institution in the multi-center 
clinical trial and the reasons ............................................................................................................................ 28 
9.3 Significance level and power of the clinical trial ....................................................................................... 28 
9.4 Predicted drop-out rate .............................................................................................................................. 28 

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9.5 Qualified/unqualified criteria of the clinical trial results ........................................................................... 29 
9.6 Criteria and reasons for terminating the trial for statistical reasons........................................................... 29 
9.7 Statistical methods for all data, including missing, unused and erroneous data (including halfway 
withdrawal by the subjects or the investigators) and treatment of unreasonable data ..................................... 29 
9.8 Procedures for reporting deviation of original statistical plan ................................................................... 30 
9.9 Criteria for selection of subjects incorporated into the analysis and its reasons ........................................ 30 
10 Data Management ................................................................................................... 30 
10.1 CRF .......................................................................................................................................................... 30 
10.2 Device data in CRF .................................................................................................................................. 31 
10.3 Data quality control ................................................................................................................................. 31 
11 Feasibility Analysis ................................................................................................ 31 
11.1 Possibility analysis of success ................................................................................................................. 31 
11.2 Analysis of failure possibility .................................................................................................................. 31 
12 Quality control of clinical trial ............................................................................... 32 
12.1 Monitoring of clinical trial ....................................................................................................................... 32 
12.2 Training .................................................................................................................................................... 32 
12.2.1 Study site training ......................................................................................................................... 32 
12.2.2 Training for monitor of the sponsor .............................................................................................. 33 
12.2.3 Support provided by the sponsor for the clinical trial site to be examined by the supervision 
department ............................................................................................................................................... 33 
13 Ethical issues and informed consent for the clinical trial ...................................... 33 
13.1 Ethic considerations ................................................................................................................................. 33 
13.2 Approval of trial protocol ........................................................................................................................ 33 
13.3 The process and text of informed consent ............................................................................................... 33 
14 Provisions on reporting Adverse Events and Device deficiencys.......................... 34 
14.1 Device deficiency .................................................................................................................................... 34 
14.2 Adverse event........................................................................................................................................... 34 
14.3 Adverse device events .............................................................................................................................. 34 
14.4 Serious adverse events ............................................................................................................................. 34 

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14.5 Serious adverse device events.................................................................................................................. 35 
14.6 Unexpected adverse device events........................................................................................................... 35 
14.7 Death of subject ....................................................................................................................................... 36 
14.8 Reporting procedures and contact information ........................................................................................ 36 
15 Provisions for Deviations and Modifications of Clinical Trial Protocol ............... 37 
15.1 Deviations of Clinical Trial Protocol ....................................................................................................... 37 
15.2 Modification of Clinical Trial Protocol.................................................................................................... 38 
16 Direct Access to Source Data and Files ................................................................. 38 
17 Finance and Compensation .................................................................................... 38 
18 Content Covered by the Clinical Trial Report ....................................................... 39 
19 Confidentiality Principle ........................................................................................ 39 
20 Agreement on Publication of Trial Results ............................................................ 39 
21 Duties of Parties ..................................................................................................... 40 
21.1 Duties of clinical trial institutions and investigators ................................................................................ 40 
21.2 Duties of the Sponsor ............................................................................................................................... 42 
22 Statement of Investigators ...................................................................................... 47 
 

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1 Protocol Summary 
Name of study 
Clinical Trial for Pre-market Registration of Biotronik Qubic Stim Cardiac Stimulator 
Purpose of study 
To prove the clinical effectiveness and safety of Qubic Stim Cardiac Stimulator in Chinese 
population. 
Study design 
The trial is a multicenter, prospective and single-arm study. 106 appropriate subjects were 
selected from 3 study sites in China in accordance with the inclusion and exclusion criteria. 
The subjects consent to participate in the trial and sign the informed consent. The subjects 
who meet the inclusion and exclusion criteria will receive the intracardiac 
electrophysiological examination, during which the subjects will be subject to diagnostic 
electrical stimulation by the Qubic Stim Cardiac Stimulator. The subjects will also receive 
the clinical follow-up visit after cardiac electrical stimulation until they are discharged from 
the hospital. The clinical effectiveness and safety of Qubic Stim Cardiac Stimulator in 
Chinese population were proved by observing the data collected in this study. 
Sample size 
106 cases 
Study site 
3 study sites in China 
Investigational 
device 
Qubic Stim Cardiac Stimulator 
Study population 
Patients with indications for intracardiac electrophysiological examination 
Study period 
Enrollment time of the first batch of subjects: October 2020 
Expected inclusion period: 3 months 
End of follow-up: Feburary 2021 
Inclusion criteria 
1. 
Age ≥ 18 years 
2. 
Subjects who are willing to participate and sign the informed consent form，and are 
able to finish the follow-up at the study site. 
3. 
Subjects with an indication of the intracardiac electrophysiological examination(fit one 
of the following): 
 
Paroxysmal supraventricular tachycardia: atrioventricular reentrant tachycardia or 
atrioventricular node reentrant tachycardia or atrioventricular tachycardia 
 
Ventricular arrhythmia: Premature ventricular contraction or ventricular 
tachycardia. 
 
Atrial fibrillation 
 
Atrial flutter 
Exclusion criteria 
1. Previous cases of unsuccessful radiofrequency ablation or recurrence 
2. Pregnant and/or lactating women 
3. Acute or severe systemic infection was present within 7 days prior to the intracardiac 
electrophysiological examination 
4. Liver and kidney functions were obviously abnormal within 7 days prior to the 

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intracardiac electrophysiological examination 
5. Obvious bleeding tendency or blood system disease 
6. Cancer and terminal disease 
7. Combined with severe organic cardiovascular disease 
8. Cerebral apoplexy and other cerebrovascular diseases within the past 3 months 
9. Thromboembolic disease 
10. Subjects who are participating in other interventional clinical trials 
Primary 
clinical 
observation 
indexes 
The success rate of the Qubic Stim cardiac stimulator to send diagnostic electrical 
stimulation to the heart. The success standard refers to that all the main functions of the 
cardiac stimulator meet the success standards, including: 
1. 
Programmed extrastimulation (PES) 
Expected clinical effect: PES can effectively pace the heart at a set rate of stimulation. 
2. 
High Rate (Burst) 
Expected clinical effect: when the tachycardia is induced or terminated by high rate 
stimulation, this device can effectively pace the heart according to the set stimulating 
frequency. 
3. 
Measurement of Sinus node recovery time (SNRT) 
Expected clinical effect: SNRT can be measured. 
This trial will conduct cardiac electrical stimulation by the main functions of the cardiac 
stimulator above. Only when the above three functions all reach the standards in particular 
subjects, it is judged as stimulation success. The main  evaluation index corresponds to the 
proportion of the patients who achieve the success standards. 
Secondary clinical 
observation index 
Serious device adverse events caused by cardiac stimulator 
Follow-up 
arrangement 
1. 
Baseline evaluation: when the subjects were enrolled. 
2. 
Electrical cardiac stimulation: the period during which the subjects receive the 
intracardiac electrophysiological examination. 
3. 
Pre-discharge assessment 
Sponsor 
BIOTRONIK SE & Co.KG 

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2 Sponsor Information 
Name of sponsor 
BIOTRONIK SE & Co.KG 
Address of sponsor 
Woermannkehre 1 
12359 Berlin, Germany 
Contact information of 
sponsor 
Mathias Freudigmann +49 (0) 30 68905 1248 
mathias.freudigmann@biotronik.com 
Relevant qualification 
documents of sponsor 
TUV certification of production enterprise quality system 
Name of agent 
BIOTRONIK (Beijing) Medical Device Limited 
Address of agent 
Room 1122, 1123AB and 1125, Interchina Commercial Building, 
No. 33, Dengshikou Street, Dongcheng District, Beijing 
Contact information of agent 
Lan Chen 13811648209 
Relevant qualification of agent 
Unified social credit code certificate of enterprise and business 
license 
 
3 List of All Clinical Trial Institutions and Investigators in Multicenter Clinical 
Trial 
Code of clinical 
trial institutions 
Name of clinical trial institutions 
Investigator 
Title 
Contact information 
01 
China-Japan Friendship Hospital 
Yifeng Zhou 
Chief Physician 
13811750398 
02 
TEDA International Cardiovascular 
Hospital 
Jian Zhang 
Chief Physician 
13920642460 
03 
The First Affiliated Hospital of 
Nanchang University 
Jingtian Peng 
Chief Physician 
13007227250 
4 Purpose and Content of Clinical Trial 
4.1 Purpose 
It is intended to prove the clinical effectiveness and safety of Qubic Stim Heart Stimulator in 
Chinese population. 

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8 
4.2 Content 
This is a multicenter, prospective and single-arm study. 106 appropriate subjects were selected 
from 3 study sites in China in accordance with the inclusion and exclusion criteria. The subjects 
who meet the inclusion and exclusion criteria will receive the intracardiac electrophysiological 
examination after signing the informed consent, during which the subjects will be subject to 
diagnostic electrical stimulation by the Qubic Stim Cardiac Stimulator. The subjects will also 
receive the clinical follow-up after cardiac electrical stimulation until they are discharged from the 
hospital. The clinical effectiveness and safety of Qubic Stim Cardiac Stimulator in Chinese 
population were further demonstrated and proved by observing the data collected in this study. 
 
5 Background Information of Clinical Trial 
Intracardiac electrophysiological (EP) examination is widely used to evaluate cardiac 
conduction disturbance and arrhythmias. The risks associated with this procedure, particularly the 
use of an extracorporeal programmed stimulator, are generally acceptable and the patient benefits 
are considered to outweigh the risks. Diagnostic EP examination is usually combined with the 
treatment of a diagnosed heart disease, such as catheter ablation of arrhythmia. In addition, the 
results of EP examination may indicate the need for specific drugs or implantation of a pacemaker 
or cardioverter defibrillator for treatment. 
As a manufacturer of implantable cardiac stimulator and ablation catheter, BIOTRONIK SE 
& Co.KG has marketed more than 1,300 extracorporeal programmed stimulators for EP 
examination since 1982, including UHS 20 device and the updated UHS 3000. Both of the devices 
are used for clinical EP examination. Qubic Stim device is an iterative product of UHS 3000 
Universal Cardiac Stimulator. The two devices have similar operation function, intended use and 
indications. Other medical device manufacturers active in the cardiac EP diagnosis and treatment 
market also provide a series of extracorporeal programmed stimulators, which are used in the same 
clinical environment as Qubic Stim device. 
The clinical evaluation of Qubic Stim Stimulator (software release version UHS_SE1.9; 
UHS_BE1.8) and PK-128 patient-end cable is provided by BIOTRONIK SE & Co.KG in 
accordance with the requirements of MEDDEV 2.7.1 Guidelines for Clinical Evaluation of Medical 
Devices. No uncertain risk emerged in the risk management process of Qubic Stim device and 
PK-128 patient-end cable based on published literature in the public domain, manufacturer's clinical 

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8 
experience and results of device availability test. The safety and performance of the device are well 
validated by clinical evaluation. This medical device meets the basic requirements of European 
Union (EU) Medical Device Directive. In Europe no further clinical data is needed to prove the 
safety of Qubic Stim device and PK-128 patient-end cable. This device is clinically equivalent to 
the most advanced commercially available competitor device, and Qubic Stim performance is 
suitable for the most advanced EP diagnostic stimulation. 
 
6 Product Characteristics, Structure Composition, Operating Principle, Action 
Mechanism of Product and Trial Stretch 
6.1 Product characteristics 
Qubic Sim system is an active and non-invasive medical device runs on software, which is 
mainly used in combination with other diagnostic medical devices. The Qubic Stim control units 
and stimulation units are provided in a non-sterile manner and are not suitable for sterilization. 
PK-128 patient-end cable is sterile and can be re-sterilized in sterile area. However, the 
patient-end cable is connected to other equipment (see Figure 1) in current clinical practice, in 
which case the patient-end cable does not enter the sterile area and does not need sterilization. 
The Qubic Stim device is used for invasive cardiac surgery based on its intended application. 
6.2 Product structure, operating principle and action mechanism 
6.2.1 System structure and settings 
Qubic Stim system includes control unit and stimulation unit, which are connected with each 
other via Ethernet cable (VK-118). Although software release version UHS_SE1.9; UHS_BE1.8 
supports the single control unit, stimulation unit hardware is still used to connect two separate 
control units for future development. The stimulation unit is connected to other devices through 
PK-128 patient-end cable. An overview of typical device connection including the Qubic Stim 
system and PK-128 patient cable is shown in Figure 1. Details about PK-128 patient-end cable are 
shown in Figure 2. 
 

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8 
 
Fig. 1: Typical setting of electrophysiological examination and catheter ablation 
 

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Fig. 2: PK-128 patient-end cable 
6.2.2 Operating principle and action mechanism 
Qubic Stim system is designed to provide the following stimulation modes: 
 Programmed extra stimulation (PES) 1； 
 Theta burst stimulation or high rate stimulation (Burst); 
 Measurement of sinus node recovery tim (SNRT) 
All parameters can be set on the control unit to control the device operation. The device is 
programmed and operated through the touch screen and other controls on the control unit. The 
whole operation of the system is controlled by software. The programmed stimulus plan can be 
saved and downloaded at an appropriate time. 
6.3 Trial stretch 
This Qubic Stim device is suitable for all patients who need cardiac electrophysiological 
examination which conducts diagnostic electrical stimulation on the patients during the examination. 
Therefore, the patients who have the indications of the intracardiac electrophysiological 
examination and are able to and willing to complete the intracardiac electrophysiological 
examination will participate in this trial. 
 
                                                        
1 
PES also means programmed extrastimulation, which specifically refers to adding extra stimulation to 
the heart rhythm to cause arrhythmia. Programmed extra stimulation is a more general term, including 
extra stimulation and other stimulation modes. 

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7 Indications, Contraindications and Precautions of the Product 
7.1 Indications 
The device is intended for diagnostic electrical stimulation of the heart, including induction 
and termination of tachyarrhythmia, refractory period measurements and electrical conduction 
measurements. 
Qubic Stim stimulator has the following main functions: 
 Programmed extrastimulation (PES) 
 High rate stimulation (Burst) 
 Measurement of sinus node recovery time (SNRT) 
Qubic Stim is suitable for all patients receiving electrophysiological examination. Therefore, 
the medical indication of the device is the same as that of electrophysiological examinations which 
require or do not require catheter ablation for treatment. 
7.2 Contraindications 
Qubic Stim is not suitable for permanent and non-monitoring applications as an external 
pacemaker. 
 
8 Overall Design 
8.1 Trial design 
8.1.1 Trial objective 
It is intended to prove the clinical effectiveness and safety of Qubic Stim cardiac stimulator in 
Chinese population. 

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8.1.2 Selection of test method and reasons 
A multicenter, prospective and single group method is adopted in this study. 106 subjects are 
selected from 3 study sites in China. The clinical evaluation of Qubic Stim stimulator and PK-128 
patient-end cable provided by BIOTRONIK SE & Co.KG in accordance with MEDDEV 2.7.1 
“Guidelines for Clinical Evaluation of Medical Devices” has well verified the safety and 
performance of the device. In addition, due to the mature design of the trial product, a single group 
of target values recognized by experts in the clinical professional field is used for evaluation. In a 
given clinical setting, the use of non-randomized design is acceptable. 
8.1.3 Measures to reduce and avoid bias 
In order to minimize and avoid the inherent bias of single group of target value design, the 
relatively objective and repeatable evaluation indexes are used in this study as the main evaluation 
indexes. 
8.1.4 Investigational medical device 
Components and models of investigational medical device 
Name of Component 
Model 
Stimulus unit 
Qubic Stim – EP Heart Stimulator 
Control unit 
Qubic Stim – Control Unit 
Patient cable 
PK-128 
8.1.5 Subject selection 
8.1.5.1 Inclusion criteria 
The following inclusion criteria shall be met before patients are enrolled for cardiac electrical 
stimulation: 
1. Age ≥ 18 years 
2. Subjects who are willing to participate and sign the informed consent form，and are able to 
finish the follow-up at the study site. 
3. Subjects with an indication of the intracardiac electrophysiological examination(fit one of 
the following): 

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 Paroxysmal supraventricular tachycardia: atrioventricular reentrant tachycardia or 
atrioventricular node reentrant tachycardia or atrioventricular tachycardia 
 Ventricular arrhythmia: Premature ventricular contraction or ventricular tachycardia. 
 Atrial fibrillation 
 Atrial flutter 
 
8.1.5.2. Exclusion criteria 
1. Previous cases of unsuccessful radiofrequency ablation or recurrence 
2. Pregnant and/or lactating women 
3. Acute or severe systemic infection was present within 7 days prior to the intracardiac 
electrophysiological examination 
4. Liver and kidney functions were obviously abnormal within 7 days prior to the intracardiac 
electrophysiological examination 
5. Obvious bleeding tendency or blood system disease 
6. Cancer and terminal disease 
7. Combined with severe organic cardiovascular disease 
8. Cerebral apoplexy and other cerebrovascular diseases within the past 3 months 
9. Thromboembolic disease 
10. Subjects who are participating in other interventional clinical trials 
8.1.5.3. Criteria and procedures for termination of trial / trial treatment 
When the study is completed or terminated, BIOTRONIK shall inform the investigators. 
Investigator shall return any investigational devices, equipment and relevant information they 
obtain at the request of BIOTRONIK. BIOTRONIK shall provide the final report to each study site. 
At the end of the study, BIOTRONIK will conduct a study closure visit, during which the 
BIOTRONIK shall verify the study records to ensure that the investigators can understand any 
applicable regulatory requirements, including those related to record keeping. After the date of 
termination or completion of the clinical trial, the investigators shall also keep the original 
documentation of the study for 10 years. 
(1) Suspension or early termination of study 
BIOTRONIK may terminate the study in advance or suspend the study due to the following 
circumstances: 

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BIOTRONIK monitors the safety after cardiac electrical stimulation by continuous evaluation 
of all adverse events related to cardiac stimulator. If serious adverse device events (SADE) affect 
the health and safety of the subjects, the study will be suspended until the cause of serious adverse 
device events is clarified. The study can only continue if the health and safety of the subjects are not 
affected. However, tachycardia events caused by any programmed stimulation will not cause the 
study to be suspended. Retraining is required if investigators fail to follow research protocols and 
regulations; if the investigator continues to fail to comply with the protocol and relevant regulations, 
the study will be suspended until the investigator is fully retrained and qualified. 
In case of serious failure of investigational device due to cardiac electrical stimulation, all 
study sites shall immediately terminate the study. 
(2) Follow-up requirements of subjects 
After suspension or early termination of the study, the investigator must notify all subjects 
(who may not have completed the study). The study site will ensure that attention is paid to the 
subjects. 
8.1.5.4. Enrollment time 
106 cases are expected to be enrolled in this trial, and the enrollment is planned to be 
completed 3 months after the start of the trial. If the enrollment is not completed, the whole trial 
process will be postponed. 
8.1.5.5. Expected overall duration of clinical trials and reasons for its determination 
In this study, data is collected, analyzed and reported to further determine the clinical 
effectiveness and safety of Qubic Stim cardiac stimulator in Chinese population, which provides a 
basis for the application of pre-market approval. 
All subjects who meet the inclusion and exclusion criteria will receive the intracardiac 
electrophysiological examination after signing the informed consent, during which the heart will 
be given diagnostic electrical stimulation through the Qubic Stim cardiac stimulator. The subjects 
will also receive the clinical follow-up after cardiac electrical stimulation until they are discharged 
from the hospital. 
In view of the three-month enrollment time, the whole study is expected to start in October  
2020 and end in Feburary 2021. 

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8.1.5.6 Predicted participation duration of each subject 
Each subject can be enrolled only after signing the informed consent form. After that, the 
subject will receive cardiac electrophysiology in accordance with clinical routine diagnosis and 
treatment procedures as scheduled by the investigators. When the subject completes the follow-up 
on the day of discharge, the study will be ended. 
8.1.5.7 Subject number required in the clinical trial 
This study is a prospective, multicenter, single-arm, and interventional study with a sample 
size calculation for the main clinical observation indexes. In this trial, it is planned that 106 subjects 
will be enrolled. 
8.1.6 Effectiveness evaluation method 
8.1.6.1 Description of effectiveness parameters 
Cardiac electrical stimulation is performed through the main function of the cardiac stimulator 
to achieve the corresponding expected clinical effect, which serve as the evaluation of clinical 
effectiveness. 
8.1.6.2 Methods and time selection for evaluation, record and analysis of effectiveness 
parameters 
The device is used for diagnostic electrical stimulation of the heart, including induction and 
termination of tachyarrhythmia, refractory period measurement and electrical conduction 
measurement. The main functions of cardiac stimulator include: 
1. Programmed extrastimulation (PES) 
The expected clinical effect: the heart is effectively paced by PES at a set rate of 
stimulation. 
2. High rate stimulation (Burst) 
The expected clinical effect: when the tachycardia is induced or terminated by high-rate 
stimulation, the device can effectively pace the heart at a set rate of stimulation. 
3. Measurement of sinus node recovery time (SNRT) 
The expected clinical effect: the sinus node recovery time can be measured. 
The success rate of the Qubic Stim cardiac stimulator to send diagnostic electrical 
stimulation to the heart. The success standard refers to that all the main functions of the 
cardiac stimulator meet the success standards. Cardiac electrical stimulation is performed 

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by the above main functions of the cardiac stimulator in this trial, and when the above three 
functions in particular subjects are up to the standards, it is judged as stimulation success. 
The main evaluation index corresponds to the proportion of the patients who reach the 
success standards. 
The target value for the success of this trial is defined as not less than 90%. 
8.1.7 Safety evaluation method 
8.1.7.1 Description of safety parameters 
Serious adverse device events rate (PSADE) is used in this trial to evaluate clinical safety of 
Qubic Stim cardiac stimulator. 
8.1.7.2 Method and time selection for valuation, record and analysis of safety parameters 
All adverse events shall be recorded throughout the study. However, only the serious adverse 
events that are definitely, likely or possibly related to Qubic Stim cardiac stimulator will become 
the basis of SADE event rate. 
SADE related to Qubic Stim cardiac stimulator is defined but not limited to: serious adverse 
device events caused by failure to start-up, current failure to output, leakage current and other 
reasons. These will be recorded as SADE related to Qubic Stim cardiac stimulator. But in cases 
where electrical stimulation is known to cause potentially life-threatening arrhythmias, many times 
inducing these arrhythmias is the purpose of an electrophysiological examination. Therefore, any 
tachycardia events caused by programmed electrical stimulation in this study will not be included in 
SADE. 
The important parameter PSADE is the rate of serious adverse events that may be related to 
Qubic Stim cardiac stimulator for each subject, which is equal to the number of SADE divided by 
the number of subjects. 
8.1.8 Other concerned data and evaluation indicators 
In addition to collecting concerned data supporting predefined, subjects will be followed up 
until discharge after cardiac electrical stimulation, and further information will be collected at the 
same time, during which the follow-up data will be recorded on the CRF.  
8.1.8.1 Adverse event 
In addition to SADE, adverse events throughout the study shall be recorded and reported. The 
potential risks associated with the trial involve major complications of intracardiac 
electrophysiologic examination.  

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1. Arrhythmia: Atrial fibrillation is usually transient and does not require any treatment if 
there is no hemodynamic deterioration.If the subject is intolerant to atrial fibrillation, 
electrocardiography should be given. When ventricular fibrillation occurs, electrical 
defibrillation should be given immediately. Complete atrioventricular block occurs if the 
original bundle branch block is caused by another bundle branch block due to ablation or 
mechanical damage when the ablation catheter is near the site of the His bundle. 
2. Pulmonary embolism: A clot forms in the sheath and rushes into the vein. The femoral 
artery and femoral vein were overpressurized and bandaged for too long. Prolonged bed 
rest after surgery, varicose veins in the lower extremities, old age, and hypercoagulability 
all contribute to venous thrombosis and pulmonary embolism in the lower extremities. 
3. Systemic thromboembolism: Thrombus formation or thromboembolism may occur at the 
catheter entry site. 
4. Vagus reflex: Pain, emotional stress, insufficient blood volume and other factors lead to 
strong reflex dilation of small blood vessels, resulting in decreased blood pressure and 
rapid slowing of heart rate.The operation time is too long, the fasting time is too long, 
stimulates the heart and the blood vessel wall; During the process of pulling out the 
indwelling sheath tube and pressing to stop bleeding, neck compression is too heavy or too 
long, which may cause vagal reflex. 
5. Vascular complications: The formation of pseudoaneurysm means that the injury at the 
puncture site of the vascular wall cannot be closed, and the blood pressure enters the 
peripheral tissues to form a local hematoma. The formation of arteriovenous fistula is 
related to puncture. 
6. Bleeding: Bleeding may occur occasionally, especially during femoral operations. The risk 
of bleeding increases when the femoral artery is used as the catheter approach, especially 
in obese people. 
7. Infection: Invasive operation may lead to local infection of puncture, or in severe cases, 
systemic infection. 
8. Acute pericardial tamponade: This causes hemopericardium if it causes a rupture 
of the blood vessels in the heart wall or pericardium.If pericardial tamponade is serious, 
pericardiocentesis for decompression is required. 
In addition, the potential risk also involves the safety of the investigational device.Failure to 
comply with the investigational device safety regulations will not only cause harm to the subjects 

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and related personnel, but also damage the investigational device and other equipment. The 
following dangers may arise in the event of improper use: 
1. Failure of important device functions 
2. Personal endangerment due to electrical impact 
8.2 Trial flow chart                     
 
   No 
            
           Yes 
                          No 
                           
           Yes 
           
           
                          
 
 
 
 
 
Fig. 3 Trial flow chart 
Sign informed consent 
Exclusion 
Meet the inclusion and 
exclusion criteria 
Failure of Screening 
Cardiac electrical 
stimulation was given 
during intracar Cardiac 
electrical stimulation was 
given during intracardiac 
electrophysiological 
examinationdiac 
electrophysiological 
examination 
Follow up on the day 
of discharge 

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8.2.1 Study follow-up plan 
Specific follow-up in the study: 
1. Baseline assessment 
2. During the cardiac electrophysiological examination 
3. Assessment on the day of discharge 
Follow-up arrangement of the study: see Table 1 for details. 
Table 1 follow-up arrangements of the study 
Contents 
Baseline 
assessment 
Intracardiac 
electrophysiological 
examination 
On the day of 
discharge 
Obtaining informed 
consent (enrollment) 
X 
 
 
Demographics, physical 
condition 
X 
 
 
Indications of intracardiac 
electrophysiological 
examination 
X 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
Drugs 
X 
 
 
Cardiac electrical 
stimulation 
Keep the material related 
to cardiac electrical 
stimulation 
 
X 
 
Evaluation of medical 
device  
 
X 
 
Adverse event 
 
X  
X 
1. Baseline assessment 
Before enrollment, only subjects who sign the informed consent form and indicate the date 
are considered to be enrolled, and study-related procedures shall be carried out. The demographic 
data, indications of electrophysiological examination and medication situation shall be obtained 
and recorded. 

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All drugs taken by the subjects that may affect the cardiac pacing of electrical stimulation 
shall be recorded, including (but not limited to): 
Class I – Flecainide and propafenone 
Class II – β Receptor inhibitor 
Class III – Amiodarone and sotalol 
Class IV – Verapamil 
2. Intracardiac electrophysiological examination 
The electrophysiological examination was performed by person authorized by the investigators. 
Each study site shall use preset parameters (see Figure 4) to perform cardiac electrical stimulation, 
but for subject’s safety, the investigator decides when to terminate the stimulation according to the 
specific condition of the subject during the operation. Investigators shall keep the materials related 
to cardiac electrical stimulation, such as downloading or printing the information of cardiac 
electrical stimulation by multi-channel analyzer. 
Adverse events and device deficiencys during the electrophysiological examination shall be 
recorded. 
First aid treatment shall be prepared at the site of cardiac electrophysiological examination, 
including extracorporeal defibrillators and all other basic first aid equipment and emergency 
measures for resuscitation / cardiac arrest / asystole. 
Programmed extrastimulation (PES) 
(*: The extra stimulus S1S2S3S4 and S1S2S3S4S5 are optional) 
Incremental stimulus 
S1S1 
(atrium or ventricle) 
The circumference of the first stimulation is 400-600 MS (determined by the heart 
rate of subjects), decreased in 50ms, at a time until effective refractory period 
(ERP). 
Extra stimulus 
S1S2 
(atrium or ventricle) 
S1: 400-600ms, circumference is determined according to the heart rate of the 
subject 
S2= S1-100ms (decreased in 10 ms until ERP) 
Extra stimulus 
S1S2S3 
(atrium or ventricle) 
S1: 400-600ms, circumference is determined according to the heart rate of the 
subject 
S2: S1-100ms 
S3: S2-50ms (decreased in 10 ms until ERP) 
Extra stimulus 
S1: 500ms 

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S1S2S3S4* 
(atrium or ventricle) 
S2: 500ms 
S3: 500ms 
S4: 300ms (decreased in 10 ms until ERP) 
Extra stimulus 
S1S2S3S4S5* 
(atrium or ventricle) 
S1: 500ms 
S2: 500ms 
S3: 500ms 
S4: 500ms 
S5: 300ms (decreased in 10 ms until ERP) 
RS2 stimulus 
S2=Sinus RR-50 ms (decreased in 10 ms until ERP) 
High rate overspeed stimulation (Burst) 
High rate overspeed 
stimulation 
300ms (at least 10 times) 
Sinoatrial node recovery time (SNRT) 
500ms (duration 30s) 
Parameter of Unified stimulus intensity 
Amplitude: 5.0 V, Pulse width: 2ms 
3. Follow-up on the day of discharge 
Clinical follow-up shall be carried out on the day when the patient is discharged from the 
hospital in order to observe the short-term effects of electrostimulation for the heart. And all 
adverse events which have occurred since cardiac electrophysiology examination and until 
discharge shall be recorded. 
4. End of the study 
The study is completed after the subjects complete the follow-up on the day of discharge. For 
early termination of the study (e.g. quit, death), the cause and the date of last contact shall be 
recorded. 

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8.2.2 Device use specification 
The authorized investigators can perform a cardiac electrical stimulation test. First aid 
treatment shall be prepared at the site of an endocardial electrophysiological examination, including 
external defibrillator and all other basic first aid equipment and emergency measures for 
resuscitation /cardiac arrest /asystolia. 
8.3 Monitoring plan 
As the sponsor of this study, BIOTRONIK is responsible for carrying out appropriate 
monitoring to ensure that this study can be conducted in accordance with the study protocol and 
relevant regulations. 
BIOTRONIK shall ensure that the device is used under the direct guidance of the investigators. 
As investigators, the doctors shall comply with applicable laws and the stipulations of National 
Medical Products Administration, and implement the study in accordance with the signed study 
agreement and protocol and the requirements of Ethics Committee. Main investigators shall also 
assume the responsibility for all aspects of the study, including the work of other personnel 
involved in the study at the center. 
The monitors shall be trained, qualified and appointed by BIOTRONIK to monitor the research 
progress of the study site. The monitors shall visit the study sites at regular intervals during the 
study. BIOTRONIK may also require company personnel to participate in the monitoring and 
follow-up process so as to assist the investigators. In regular monitoring, the evaluation of study site 
includes: 
• 
Required CRF and other applicable research documents are completed and submitted. 
• 
The study site can continue to be monitored. 
• 
Clinical trial protocol is followed. 
• 
Applicable laws and regulations on the responsibilities of investigators and record 
maintenance are followed 

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9 Statistical Considerations 
9.1 Statistical design, methods, and analysis procedures 
9.1.1 Study hypothesis 
The study is a prospective, multi-center, single-group, and target-value-controlled clinical trial. 
The comparison with the target value proves that the test device meets the requirements of clinical 
application. The main endpoint index is the success rate of the Qubic Stim cardiac stimulator to 
send diagnostic electrical stimulation to the heart. The corresponding statistical hypothesis tests are:  
0
1
0
0
:
:
p
p
p
p
T
T
>
Η
≤
Η
 
Here, 
Tp  represents the success rate of the test product; and 
0
p  represents the target 
value. 
9.1.2 Statistical analysis methods 
1) Descriptive analysis: Counting data is described by frequency and constituent ratio; while 
measurement data is described by mean, standard deviation, median, the 25th and 75th quantiles, 
maximum, and minimum. 
2) Baseline demographic analysis: Descriptive analysis will be the main method. For 
subgroups comparison that may be involved, the likelihood data χ2 test will be used between 
counting data groups. When the theoretical frequency of more than 25% of the cells is less than 5, 
the Fisher exact probability method will be used. Grouped t-test is used for comparisons between 
groups with normally distributed measurement data; while Wilcoxon Rank Sum test used for 
comparisons between groups with non-normally distributed measurement data. 
3) Efficacy analysis: All patients who use the investigational product will be included in the 
analysis. For the primary efficacy indexes, the asymptotic normal method and accurate probability 
method will be used to estimate the stimulation success rate and its 95% confidence interval, and 
the lower limit of the confidence interval are compared with the set target values to determine 
whether the test product meets the needs of clinical application. Meanwhile, the Tipping Point 
method will also be used to perform a sensitivity analysis on the potential impact of missing data. 
For the filled data, the asymptotic normal method and accurate probability method are also used to 
estimate the product success rate and 95% confidence interval, respectively. The statistical analysis 
method to be used for other efficacy indexes is the same as the baseline; for intra-group 

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comparisons that may be involved in specific indexes, paired t test is used for comparisons between 
groups with normally distributed measurement data; while Wilcoxon Rank Sum test used for 
comparisons between groups with non-normally distributed measurement data; and for intra-group 
comparison of qualitative indexes, the McNemar paired x2 test is used. 
4) Safety evaluation: Adverse events are described by the number and incidence of adverse 
events; meanwhile, the specific manifestation, severity and relationship between all the adverse 
events are described in detail. 
5) For the main endpoint indexes, statistical analysis will be performed at a significance level 
of 0.025 on one side (corresponding to the one-sided confidence limit of the 95% confidence 
interval), and statistical analysis of other indexes will be performed at a significance level of 0.05 
on both sides (unless otherwise stated). All the statistical analysis will be run on SAS®9.4 statistical 
software. 
9.1.3 Statistical analysis procedures 
Relevant links involved in the statistical analysis will be in accordance with the requirements 
in ICH E9 and the relevant requirements in the "Guidelines for Biostatistics of Clinical Trials" 
issued by the National Medical Products Administration (NMPA). Meanwhile, all statistical 
analysis processes will be performed in strict accordance with the Standard Operating Procedures 
(SOP) formulated by the Medical Statistics Department of the National Center for Cardiovascular 
Diseases. 
9.2 Calculation of sample size 
9.2.1 Total sample size 
The total number of patients enrolled in this study is planned to be 106. The sample size is 
determined based on a combination of study hypothesis and estimates of expected levels of efficacy, 
and is calculated on a statistical basis. The sample size is calculated based on the primary endpoint 
index, i.e., the success rate of Qubic Stim cardiac stimulator to send diagnostic electrical stimulation 
to the heart. Due to the limited reference materials for similar products, the "Guidelines for the 
Technical Review of the Registration of Implantable Cardiac Electrode Lead Products" combined 
with the opinions and recommendations of cardiac electrophysiological clinical experts, the target 
value of the primary index is set at 90%. Meanwhile, assuming that the expected success rate of the 
investigational product can reach 98%, when the significance level of the statistical test is 0.025 on 
one side, and the assurance level is 90%, considering the largest possible drop-out rate in the study 

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is 5%, and using the accurate probability method in combination, the sample size is finally set at 
106 cases. The corresponding sample size calculation formula is: 
(
)
(
)
[
]
(
)
 
1
1
2
0
2
1
0
0
1
p
p
p
p
p
p
n
T
T
T
−
−
+
−
=
−
−
β
α
µ
µ
 
Here, 
T
p  represents the predicted success rate level of the test product and 
0
p  represents the 
corresponding target value; μ represents the quantile corresponding to the standard normal 
distribution, α  corresponds to the type I error level of the statistical test, and it is 0.025 here, while 
β  corresponds to the type II error level of the statistical test, and it is 0.1 when calculation 
(corresponding to 90% power level). 
According to the clinical practice, the estimated screening failure rate is expected to be 20%, 
so the estimated total number of screening cases is 133. 
9.2.2 Case number of each disease in the clinical trial and the determination reasons 
This trial protocol strictly limits the selected patients according to the inclusion/exclusion 
criteria. It can be considered that the current study is only conducted in patients with a single 
indication. The above 106 patients belong to the same disease group and will not be further divided. 
9.2.3 The minimum and maximum subject numbers of each clinical trial institution in the 
multi-center clinical trial and the reasons 
This trial will be conducted in multiple clinical trial institutions at the same time. In principle, 
the number of participants in centers will be distributed as evenly as possible to ensure sufficient 
center representativeness. However, considering the feasibility and actual progress of enrollment, 
the number of enrollment will be adjusted in accordance with the actual situation to ensure that the 
number of each center's participants is relatively balanced, and for a particular center, its final size 
should not exceed 50% of the total. 
9.3 Significance level and power of the clinical trial 
In this trial, the significance level and the power of the statistical test are 0.05 on both sides 
(except for otherwise stated) and the assurance degree of test is 90%, respectively. 
9.4 Predicted drop-out rate 
In the sample size design process, the largest possible drop-out rate in the study period is 
expected to be 5%. The drop-out includes all cases that ultimately cannot be included in the main 
analysis, and usually refers to significant violations of the study protocol judged by the principal 

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investigator. The possible situations include (not limited to): patients do not meet the 
inclusion/exclusion criteria; patients do not use any study-related products; patients use third-party 
products other than the study; patients do not complete follow-up as required; follow-up time 
windows exceed the set time limit; there are concomitant treatments that affect efficacy. All of the 
above will be included in the total drop-out rate. 
9.5 Qualified/unqualified criteria of the clinical trial results 
From a statistical perspective, judging whether the clinical trial results are qualified or not is 
equivalent to verifying the initial hypothesis. In this study, the primary evaluation index is the 
success rate of Qubic Stim cardiac stimulator to send diagnostic electrical stimulation to the heart. 
By comparing the trial results with pre-set target values, it is confirmed that the test product meets 
the clinical application requirements. 
In summary, the determination of the trial results will be based on the comparison between the 
test product stimulation success rate and target value. If the results show that the lower limit of the 
95% confidence interval of the test product success rate exceeds 90% (a preset target value), a 
positive result can be considered to indicate that the test product can meet the requirements of 
clinical application. 
9.6 Criteria and reasons for terminating the trial for statistical reasons 
This trial does not pre-set mid-term analysis and corresponding early termination criteria, so it 
is inapplicable here. All statistical analysis is performed after the data are collected, cleaned and 
finally locked. 
9.7 Statistical methods for all data, including missing, unused and erroneous data (including 
halfway withdrawal by the subjects or the investigators) and treatment of unreasonable data 
The statistical analysis process (procedure) is implemented in strict accordance with the 
Standard Operating Procedures (SOP) of the Medical Statistics Department of the National Center 
for Cardiovascular Diseases. Please refer to related documents for details. 
For the missing data that may appear in the study process, the analysis will deal with the 
missing main efficacy indicators. The specific treatment methods will be explained in the statistical 
analysis plan. At the same time, we will also use Tipping Point critical point method for sensitivity 
analysis of the impact of missing data. For other missing indexes, we will analyze the data that are 
actually observed directly rather than by cut-off processing. 

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Erroneous and unreasonable data will be processed in the data cleaning process before 
statistical analysis. Information on patients who withdraw from the trial by themselves or by the 
investigators will still be included into the final statistical analysis. The statistical report will detail 
all the withdrawals by the patients or the investigators, and missing primary indexes resulting from 
early withdrawals will be treated according to the above treatment strategy for missing data. 
9.8 Procedures for reporting deviation of original statistical plan 
The statistical analysis proposal needs to be confirmed by the sponsor and the principal 
investigator, and finalized before the data are locked. Prior to finalization, the initial analysis plan 
can be modified in accordance with the actual situation during the trial. In principle, the main 
analysis principles, methods and analysis sets will not be modified, and all modifications will be 
recorded. 
9.9 Criteria for selection of subjects incorporated into the analysis and its reasons 
The statistical analysis will be performed on the basis of the following analysis populations, 
which will be clearly defined before the start of the statistical analysis. The analysis populations in 
this study include: 
Full Analysis Set (FAS): An analysis set that is determined in accordance with the Intention To 
Treat principle, which will include all subjects who participates in the trial (recorded in the central 
registry) and do use the investigational product. 
Per Protocol Set (PPS): refers to all subgroups of patients who have completed the trial without 
significant protocol deviation (referring to the study subject's violation of the inclusion/exclusion 
criteria, etc.). 
The analysis of the primary efficacy indexes will be performed on the basis of the FAS and the 
PPS; all baseline demographic data and secondary efficacy analysis will be performed on the 
basis of the FAS, and the safety evaluation will also be based on the FAS. (So SS is not defined 
separately). 
 
10 Data Management 
10.1 CRF 
Original data shall be collected from each study site, recorded in CRF and then verified by 
CRF. 

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10.2 Device data in CRF 
All preset parameters of ECG stimulator shall be recorded in CRF, which can be downloaded 
or printed by multi-channel analyzer and saved as original data. 
10.3 Data quality control 
Biotronik shall verify the study data. At any time, Biotronik or the investigators approved by 
each study site shall report the completed and missing data. After CRF data is input into the 
database, the validity, consistency, deficiency and normal range of data shall be checked by the 
logic examination program. The data manager shall timely solve any problem discovered, those 
problems can be solved by making a judgment through comparing the data with that in other parts 
of CRF, as well as issuing data query table to the investigator. 
 
11 Feasibility Analysis 
11.1 Possibility analysis of success 
The safety and performance of Qubic Stim electrical cardiac stimulator has been analyzed 
through the clinical evaluation report mentioned above, and it can be inferred that the trial results 
can be extended to ordinary Chinese patients. 
Considering that the follow-up period is short and the subjects show good compliance, there 
will not be a large number of subjects lost to follow-up. Therefore, sufficient clinical data can 
obtained during the trial. 
11.2 Analysis of failure possibility 
The possibility of test failure involves: 1. The subjects fail to complete electrical cardiac 
stimulation test safely. 2. The cardiac stimulator cannot conduct pace-making and pace the heart or 
fail to measure the electrical conduction time. 3. The investigators fail to operate and collect data 
in accordance with the test requirements. In order to avoid test failure, the investigators shall be 
fully trained, the subjects shall be fully informed, and the study shall be conducted in strict 
accordance with the trial protocol. 
 

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12 Quality control of clinical trial 
12.1 Monitoring of clinical trial 
Study monitors are individuals who are appointed to be responsible for monitor the progress of 
study. The monitors are all properly trained and qualified to monitor the progress of clinical study. 
The study sponsor may appoint additional monitors at any time during the study. For additional 
information about the staff responsible for monitoring, please contact the sponsor. 
The monitoring of the sponsor (or the representative) will visit each investigator prior to any 
procedure to ensure compliance with the following criteria: 
The investigators understand and accept the obligation to conduct clinical study in accordance 
with the study protocol and applicable regulations, and hereby sign the clinical study agreement. 
The investigators and their staff have sufficient time and facilities to conduct the study, and 
can access to a sufficient number of appropriate subjects for trial. 
Original material shall be provided to prove the appropriateness of informed consent procedure, 
compliance with the study protocol, adequate reporting and follow-up of adverse events, accuracy 
of data collected in CRF and device information. The investigators/study site will be approved to 
access to such records. The study site shall maintain the signature log of monitoring visit. The 
investigators shall agree to take sufficient time to cooperate with the monitoring process and the 
investigators and/or study coordinator shall be present during the monitoring visit. The investigators 
shall provide the study supervisor with appropriate working environment for the purpose of 
reviewing study related documents. 
12.2 Training 
12.2.1 Study site training 
All investigators/testing personnel shall participate in the training provided by the sponsor, 
which can be conducted in the form of investigator meeting, study site launch visit or other 
appropriate training form. Telephone training can also be carried out when necessary. The training 
for investigators/testing personnel includes but is not limited to protocol requirements, use of test 
equipment, filling in of EMR report form and responsibilities of testing personnel. All trained 
investigators/testing personnel shall sign a training log (or similar form) after training. Before 
signing the training log, the investigators/testing personnel shall not carry out any trial-related work 
beyond the treatment standards of the study site. 

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The investigators shall accept the training on device related knowledge organized by the 
sponsor. 
12.2.2 Training for monitor of the sponsor 
The sponsor and/or designated monitor shall accept the training on relevant protocol, CRF and 
use of test equipment (if applicable) and the training process will be documented in written 
procedure. 
12.2.3 Support provided by the sponsor for the clinical trial site to be examined by the 
supervision department 
If the supervision department contacts the investigators on matters related to this clinical trial, 
the investigators shall promptly notify the sponsor and inform the Ethics Committee as appropriate. 
During examination, the investigators and study coordinator shall be present to respond to 
reasonable requests and examination queries. The investigator shall provide the sponsor with a copy 
of all correspondence that may affect the inspection of this clinical trial (for example, observations 
and warning letters for inspection). The sponsor may provide any necessary assistance to the 
supervision department for examination. 
 
13 Ethical issues and informed consent for the clinical trial 
13.1 Ethic considerations 
Clinical trial of medical device shall be carried out in accordance with ethical guidelines 
formulated in the Declaration of Helsinki of World Medical Assembly, GCP (Good Clinical 
Practice) for Medical Devices, and ISO14155. All parties involved in the clinical trial shall assume 
corresponding ethical responsibilities in accordance with their respective responsibilities in the trial. 
13.2 Approval of trial protocol 
This trial protocol does not need to be approved based on the provisions of State 
Administration for Market Regulation. 
13.3 The process and text of informed consent 
In accordance with the Declaration of Helsinki, GCP (Good Clinical Practice) for Medical 
Devices, and ISO14155, the subjects should sign the informed consent form prior to enrollment. 
Before the subjects participate in the clinical trial, the investigators shall fully explain the details of 
clinical trial, including known and foreseeable risks and possible adverse events, to subjects or 

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guardians of persons without or with limited capacity for civil conduct. After full and detailed 
explanation, the subjects or guardians thereof shall sign their names and the date on the informed 
consent, and the investigators shall also sign the name and date on the informed consent. 
 
14 Provisions on reporting Adverse Events and Device deficiencys 
14.1 Device deficiency 
Device deficiency refers to unreasonable risks that may endanger human health and life safety 
in the normal use of medical devices during clinical trials, such as label errors, quality problems, 
faults, etc. 
14.2 Adverse event 
Adverse event (AE) refers to any adverse medical events, unexpected diseases or damages, and 
adverse clinical events (including abnormal laboratory results judged by physicians with clinically 
significant) related or not related with the investigational device which occurred in the trial process. 
AEs include all events related with the medical devices and surgeries. 
During study, the symptoms presented by the subjects due to a pre-existing condition or 
condition prior to enrollment are not classified as AEs, for example, the attach frequency or severity 
kept unchanged. 
The planned examinations that do not harm the health of subjects were not classified as AEs, 
e.g., regular cancer-preventive examination. 
14.3 Adverse device events 
Adverse device event (ADE) refers to adverse events related to the use of medical devices 
including all adverse events caused by the insufficient instructions for use, device application, 
installation, operations, or any function failures, as well as all adverse events caused by wrong use 
or intentional abuse use. 
 
Adverse Device Event (ADE): Adverse events caused or possibly caused by heart stimulator. 
 
Surgery-related ADE: Adverse events related or possibly related with surgical operations. 
14.4 Serious adverse events 
Serious adverse event (SAE) refers to adverse events occurring during the clinical trial which 
caused one of the following conditions: 

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 Death 
 Serious aggravation of the health status, including: 
 
Lethal diseases or damages; 
 
Permanent defect of body structure or body function 
 
Hospitalization treatment or prolonged hospital stays 
 
Requiring medical or surgical intervention to prevent the permanent defect of body 
structure or body function; 
 Fetal distress, fetal death, or congenital deformity, congenital defect, and etc. 
The planned hospitalization before enrollment, surgeries required in the trial protocol, and 
events not causing serious aggravation of the health status are not regarded as SAEs. The medical or 
surgical interventions implemented to prevent the occurrence of life-threatening conditions are 
regarded as SAEs. For instance, the hospitalization due to pneumonia or hospitalization because of 
any surgical intervention is regarded as SAE. A new event occurring during hospitalization which 
prolonged the hospital stay (e.g., atrial fibrillation requiring cardioversion) is regarded as a new 
SAE, because two events had different diagnoses. The hospitalization before the aggravation of the 
health status (e.g., hospitalization due to the planned angiography) is not regarded as SAE. 
14.5 Serious adverse device events 
Serious adverse device event (SADE) refers to any adverse device events causing SAE 
consequences and characteristics. 
Cardiac electrical stimulation-related SADE is the basis for the calculation of SADE rate 
endpoint. Endpoint-related SADEs including but not limited to serious adverse device events caused 
by failure to power on and output current, and current leakage, etc. 
14.6 Unexpected adverse device events 
All devices are subject to problems or breakdowns. Unexpected adverse device events (UADE) 
refers to any serious adverse events that threaten health or safety, or any life or death, caused by or 
related to a medical device, and the event, the problem, the nature of the death, the severity or 
extent of the morbidity has not previously been confirmed in the clinical trial protocol, or any other 
unexpected serious problems associated with the medical device detriment the subject’s rights, 
safety or health. It is important to note that device failure due to product abuse is not considered an 
unexpected adverse device event. 

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14.7 Death of subject 
If a subject died during the study, as much information as possible shall be obtained so that 
BIOTRONIK can report the details of the death.  
If any, please provide the following available information: 
 
Cause of death 
 
Date and time of death 
 
Place of death 
 
Identify the heart rhythm at the time of death (if possible) 
 
Any other circumstances at the time of death 
 
Declare whether it is a device or operation related event 
 
The approximate time interval from the start of the event to death 
14.8 Reporting procedures and contact information 
 
Regarding adverse events and device deficiency, the reporting procedures of all parties shall 
comply with the specific requirements of the “Good Clinical Practice for Medical Devices” 
(the State Food and Drug Administration's National Health and Family Planning Commission 
Order 25 of the People's Republic of China). 
 In the event of a serious adverse event in a clinical trial, the investigator shall immediately 
take appropriate treatment measures for the subject, and at the same time report in writing 
to the administrative department of medical device clinical trials of the affiliated clinical 
trial institution, and notify the sponsor in writing. The administrative department for 
clinical trials on medical devices shall, within 24 hours, report in writing to the relevant 
ethics committee and to the food and drug regulatory department and health and family 
planning department of the province, autonomous region or municipality directly under the 
central government where the clinical trial institution is located. In the event of death, the 
clinical trial institution and investigator shall provide the ethics committee and the sponsor 
with all required information. 
 For serious adverse events and may result in serious adverse events equipment defects, the 
sponsor shall, within 5 working days after receiving the record by the food and drug 
supervision and administration department and the health department in charge of family 
planning report, at the same level at the same time to participate in the test of other 

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institutions and researchers, clinical trial and its medical instrument clinical trial 
management department timely notify the clinical trial institution's ethics committee. 
 
 
Contact person of the sponsor: Lan Chen 
Tel:010-65223851 
E-mail: lan.chen@biotronik.com 
 
15 Provisions for Deviations and Modifications of Clinical Trial Protocol  
15.1 Deviations of Clinical Trial Protocol 
The investigators shall conduct study in accordance with the study agreement and protocol. 
The investigators shall notify BIOTRONIK and the Ethics Committee within 5 days in writing of 
any significant deviation from the study protocol due to the protection of life or the maintenance of 
the subject’s health in an emergency. Unless it is an emergency, significant deviations from the 
study protocol shall be approved by the BIOTRONIK in advance. 
BIOTRONIK divides the cases of non-conforming study protocol into violation and deviation: 
Protocol violations are cases of non-compliance with study protocol requirements and/or regulatory 
guidelines and are generally more serious in nature. The scientific reliability of the protocol and/or 
the rights, safety or health of the subject is potentially affected by protocol violations. 
Protocol violations including but not limited to the following aspects: 
 Without the consent of the subject 
 Unauthorized investigators conduct clinical trials 
 The enrollment criteria of subjects and protocol requirements were violated, which affected 
the important data of study design 
The study site shall report the above situation to the Ethics Committee, fill out the protocol 
deviation form in the CRF, and provide a copy of the report submitted to the Ethics Committee to 
the BIOTRONIK. 
Protocol deviations are deviations from study protocol requirements due to unavailability or 
inaccessibility of data. 

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The study site shall fill out the protocol deviation form in the CRF and submit it in accordance 
with the requirements of each Ethics Committee. 
15.2 Modification of Clinical Trial Protocol 
All modifications to the clinical trial protocol shall be submitted to the corresponding Ethics 
Committee for discussion and approval before implementation. 
 
16 Direct Access to Source Data and Files 
Originals or copies of all clinical results, observations and other activities throughout the 
clinical trial shall be recorded and kept in the medical history of each enrolled subject. For the data 
recorded on the CRF, the corresponding source data shall be shown on the medical history (source 
file).  
The medical history (source file) shall include but not limited to the following information: 
 
Informed consent date  
 
Subjects participate in clinical trials  
 
Population characteristics  
 
Dated discharge report 
 
Medical history record and previous cardiovascular medications 
 
Records of cardiac electrical stimulation 
 
All adverse events: Diagnosis and symptoms, start and end dates, severity, measures taken, and 
prognosis 
 
Concomitant medication (cardiovascular medications) 
 
Completion or withdrawal date of clinical trial 
 
17 Finance and Compensation 
The sponsor of the trial is BIOTRONIK SE & Co.KG, and all expenses related to the study 
shall be provided by BIOTRONIK (Beijing) Medical Device Limited. If the subject is physically 
harmed due to the participation in this study, BIOTRONIK (Beijing) Medical Device Limited (on 

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behalf of BIOTRONIK SE & Co.KG) shall bear reasonable treatment costs and provide 
corresponding compensation in accordance with Chinese laws. 
 
18 Content Covered by the Clinical Trial Report 
The clinical trial report is consistent with the clinical trial protocol, which mainly includes the 
following contents: 
General information; abstract; introduction; clinical trial purpose; clinical trial method; clinical 
trial content; clinical general information; investigational medical devices and predicate medical 
devices or predicate diagnosis and treatment method; adopted statistical analysis methods and 
evaluation methods; clinical evaluation criteria; organizational structure of clinical trials; 
description of ethical situation; clinical trial results; adverse events found in clinical trials and their 
treatment; analysis and discussion of clinical trial results, especially indications, scope of 
application, contraindications and precautions; conclusions of clinical trial; existing problems and 
suggestions for improvement; list of trial personnel; other situations that require to be explained. 
 
19 Confidentiality Principle 
The personal data of the subjects participating in the trial shall be kept confidential, but the 
Ethics Committee, the Medical Products Administration Department, the Health and Family 
Planning Administration Department or the sponsor may access the personal data of the subjects 
participating in the trial in accordance with the prescribed procedures when the work requires. 
 
20 Agreement on Publication of Trial Results 
The sponsor has exclusive ownership of the trial data and results. During the clinical trial, the 
sponsor has the right to access and use all data and results of the trial. Individual clinical trial 
centers are not allowed to publish and/or report their results until the results of all center are 
published and/or reported. The sponsor agrees that the leading investigators of the trial will publish 
the results of the clinical trial. 
 

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21 Duties of Parties 
21.1 Duties of clinical trial institutions and investigators 
Before the clinical trial, the clinical trial management department of medical devices of clinical 
trial institutions shall cooperate with the sponsor to submit an application to Ethics Committee and 
submit relevant document in accordance with the regulations. 
Clinical trial institutions shall properly keep clinical trial records and basic documents as 
agreed with the Sponsor. 
Investigators shall ensure that personnel involved in the trial are familiar with principles of 
medical devices for trial, scope of application, product performance, operational methods, 
installation requirements and technical indicators, understand pre-clinical research data and safety 
data of investigational medical devices, and master prevention and emergency treatment methods 
for risks generated in clinical trial. 
Investigators shall ensure that all participants of clinical trial fully understand clinical trial 
protocol, relevant regulations, characteristics of medical devices for trial and duties related to 
clinical trial, sufficient subjects in clinical trial in accordance with inclusion criteria of clinical trial 
protocol, and enough time to safely conduct and complete clinical trial in accordance with relevant 
provisions within trial period agreed herein. 
Investigators shall strictly obey clinical trial protocol and shall not deviate from the protocol or 
substantially change the protocol without consent of the sponsor and Ethics Committee or without 
approval of National Medical Products Administration. However, in case that subjects are under 
danger which are required immediately eliminated, it can also be reported in writing afterwards.  
Investigators shall be responsible for recruiting subjects and communicating with subjects or 
their guardians. Investigators shall be responsible for explaining to the subject the details of the 
investigational medical device and clinical trial, informing subjects of potential benefits and known 
foreseeable risks, and obtaining dated informed content signed by subjects or their guardians. 
The investigator or other personnel participating in the study shall not force or otherwise 
induce the subject to participate in the study. 
In case investigators find adverse events unexpected for investigational medical devices in 
clinical trial, they shall modify relevant content of informed consent with the sponsor, and the 
affected subjects or their guardians shall resign on the modified informed consent for confirmation 

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after the modified informed consent is submitted to Ethics Committee in accordance with relevant 
working procedures for review and approval. 
Investigators shall be responsible for making medical decisions related to clinical trial. In the 
event of adverse events related to clinical trial, clinical trial institutions and investigators shall 
ensure that adequate and timely treatment and management are provided to the subject. The 
investigator shall inform the subject of any complications that require treatment or management. 
In case of serious adverse events in clinical trial, investigators shall take proper therapeutic 
measures for subjects immediately and report them to medical device clinical trial management 
department of clinical trial institutions to which it belongs in written form and inform sponsor of it 
in same way. Medical devices clinical trial management department shall report to the 
corresponding Ethics Committee, medical products administration department of provincial, 
autonomous region and municipality directly under the central government and Health and Family 
Planning Department where the clinical trial institution is located. In case of death incidents, 
clinical trial institutions and investigators shall submit all dossiers required to Ethics Committee and 
the sponsor. 
Investigators shall record all adverse events and device deficiencys found in clinical trial 
process, jointly analyze causes of events with the sponsor, formulate written analysis report, give 
opinions on continuing, suspending, or terminating the trial, and report them to Ethics Committee 
for review through clinical trial management department of medical devices of clinical trial 
institutions.  
Investigators shall ensure that clinical trial data are accurately, completely, clearly and 
promptly recorded in CRF. The CRF shall be signed by investigators. In case of any modification of 
data, CRF shall be signed and dated by investigators. Meanwhile original records shall be kept and 
clearly identifiable. 
Clinical trial institutions and investigators shall ensure that data, document and records for 
clinical trial are authentic, accurate, accurate and safe. 
The clinical trial institutions and investigator shall be subject to the sponsor's monitoring, 
verification, and the supervision of the ethics committee, and shall provide all required records 
relating to the trial. In case of medical products administration department and Health and Family 
Planning Department designate monitors to conduct inspections, clinical trial institutions and 
researchers shall cooperate.  

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In case that the clinical trial institutions and investigators find that risks may overweight the 
potential benefits or have obtained the result to judge safety and effectiveness of medical devices 
for trial, which requires suspension or termination of clinical trial, they shall inform the subjects, 
and ensure that subjects receive proper treatment and follow-up. At the same time, provide written 
explanation in details as specified, and report it to medical products administration department of 
the province, autonomous region or municipality directly under the central government where it is 
located if necessary. 
Investigators shall promptly inform subjects after receiving notice of suspending or 
terminating clinical trial from the sponsor or Ethics Committee and ensure that they can receive 
proper treatment and follow-up. 
In case that the sponsor violates the relevant regulations or requests to change the test data and 
conclusions, clinical trial institutions and investigators shall report it to medical products 
administrative department of the province, autonomous region or municipality where it is located or 
National Medical Products Administration.   
At the end of the clinical trial, the investigator shall ensure that all records and reports are 
completed. Meanwhile, investigators shall ensure that numbers of investigational medical devices 
received conform to that of medical devices used, wasted and returned, and that the remaining 
experimental medical devices are properly disposed and documented. 
The investigators may, in accordance with the needs of clinical trials, authorize relevant 
personnel to conduct recruitment of subjects, continuous communication with subjects, record of 
clinical trial data and management of the investigational medical devices, etc. The investigators 
shall conduct relevant training and develop appropriate documentation for their authorized 
personnel. 
21.2 Duties of the Sponsor 
The sponsor is responsible for initiating, applying, organizing, and auditing clinical trials, and 
is responsible for the authenticity and reliability of clinical trials. The Sponsor is usually a medical 
device manufacturer. In case that the Sponsor is an overseas institution, it shall have a designated 
agent in China in accordance with relevant provisions. 
The Sponsor shall be responsible for formulating and modifying investigator manual, clinical 
trial protocol, informed consent, CRF, relevant standard operating procedure and other documents 
and organizing and conducting training required for clinical trial. 

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The sponsor shall select the testing institutions and investigators among the qualified 
investigational medical device clinical testing institutions in accordance with the characteristics of 
the medical device for testing. Before signing a clinical trial agreement with clinical trial 
institutions, the sponsor shall provide clinical trial institutions and investigators with the latest 
investigators manual and other relevant documents for their decision on whether to undertake this 
clinical trial. 
Investigator manual shall include the following contents: 
(1) Basic information of the sponsor and investigators; 
(2) Overview of investigational medical devices; 
(3) Summary and evaluation supporting intended use of investigational medical devices and 
rationale for clinical trial design; 
(4) Declaration that the manufacture of investigational medical devices conforms to the 
requirements of the applicable medical device quality management system. 
The Sponsor shall not exaggerate mechanism and effectiveness of investigational medical 
devices in clinical trial protocol. 
During the clinical trials, when the sponsor receives important information affecting the 
clinical trial, the investigators’ manual and related documents shall be revised in time, and 
submitted to the Ethic Committee for review and approval via the medical device clinical trial 
management department of clinical trial institutions. 
The sponsor shall reach a written agreement with the clinical trial institutions and the 
investigators on the following items: 
(1) The clinical trials are conducted in accordance with relevant laws and regulations and 
clinical trial protocols, and accept audits, verifications and inspections;  
(2) The data recording and reporting procedures are followed; 
(3) Basic documents relevant to clinical trial are kept no less than the legally-stipulated time, 
until the sponsor notifies clinical trial institutions and investigators that the documents are not 
necessary. 
(4) After being approved by the Ethics Committee, the sponsor shall be responsible for 
providing the clinical trial institutions and investigators with the investigational medical device, and 
determining the transportation conditions, storage conditions, storage time, validity period, etc.; 

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(5) The investigational medical device shall be of qualified quality, easily identifiable, 
correctly coded and labeled with a special sign of “For trial”, and shall be properly packaged and 
stored in accordance with the requirements of the clinical trial protocol; 
(6) The sponsor shall formulate the relevant standard operating procedures for the quality 
control of clinical trials, such as the transportation, reception, storage, distribution, treatment and 
recovery of the investigational medical device, which shall be followed by clinical trial institutions 
and investigators. 
The sponsor is responsible for the safety of the investigational medical device used in the 
clinical trial. When it is found that the safety of the subjects may be affected or the implementation 
of the trial may change the approval of the Ethics Committee for continuing the trial, the sponsor 
shall immediately notify all clinical trial institutions and investigators and make corresponding 
treatment. 
If the sponsor decides to suspend or terminate the clinical trial, it shall notify the clinical trial 
management department of medical devices of all clinical trial institutions within 5 days, and 
explain the reasons in writing. The medical devices clinical trial management department of clinical 
trial institutions shall timely notify the corresponding investigators and Ethics Committee. The 
suspended clinical trial shall not be resumed without the consent of the Ethics Committee. After the 
completion of the clinical trial, the sponsor shall inform the medical products administration 
department of the province, autonomous region or municipality where it is located in writing. 
The sponsor shall ensure that all investigators implement the clinical trial strictly in accordance 
with the clinical trial protocol, and shall timely point out and correct any non-compliance of the 
clinical trial institution and investigators with the relevant laws and regulations, this Standard and 
the clinical trial protocol. In case that the situation become serious or persists, the clinical trial shall 
be terminated and reported to the NMPA and the medical products administrative departments of 
province, autonomous region or municipality directly under the central government where the 
clinical trial institution is located. 
The sponsor shall bear the cost of treatment and corresponding economic compensation for the 
subjects who suffer injury or death related to the clinical trial, except for the damage caused by the 
fault of the medical institution and its medical personnel in the diagnosis and treatment activities. 
The sponsor shall be responsible for the supervision of the clinical trial and selection of 
qualified supervisors to perform the supervision duties. 

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The number of supervisors and the time of supervision shall depend on the complexity of the 
clinical trial and the number of institutions participating in the clinical trial. 
The supervisors shall have the corresponding professional backgrounds in clinical medicine, 
pharmacy, biomedical engineering and statistics and receive necessary training. The supervisor 
shall be familiar with the relevant laws and regulations and this specification, as well as non-clinical 
information of the investigational medical device and clinical information of predicate products, 
clinical trial protocol and relevant documents. 
In order to ensure the quality of the clinical trial, the sponsor can organize monitors who are 
independent of the clinical trial and have corresponding training and experience to inspect the 
implementation of the clinical trial and evaluate whether the clinical trial meets the requirements of 
the trial protocol. 
Inspection can be used as part of the routine work of clinical trial quality management of the 
sponsor, as well as to evaluate the effectiveness of the supervision activities, or to carry out 
verification for serious or repeated clinical trial protocol deviations, suspected fraud, etc.. 
For serious adverse events and device deficiency that may cause serious adverse events, the 
sponsor shall report to the filed medical product administration department and the health and 
family planning department at the same level within 5 working days after being informed, and shall 
also report to other clinical trial facilities and investigators participating in the trial, and timely 
notify the Ethics Committee of the clinical trial facility through the clinical trial management 
department of its medical device. 
If the sponsor adopts electronic clinical database or remote electronic clinical data system, it 
shall ensure the clinical data controlled and true, and formulate complete verification documents. 
For multicenter clinical trials, the sponsor shall ensure that documents are formulated before 
the clinical trials and that the responsibilities of the coordinator and other investigators are clearly 
defined. 
For multicenter clinical trials, the sponsor shall develop standard operating procedures in 
accordance with the clinical trial protocol, and organize the training on the clinical trial protocol and 
the use and maintenance of the investigational medical devices for all the investigators participating 
in the trial, so as to ensure the consistency in the implementation of the clinical trial protocol and 
the use of the investigational medical devices. 

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In multicenter clinical trials, the sponsor shall ensure that the design of the Case Report Form 
is rigorous and reasonable, so that all data can be obtained by the coordinating investigator from 
each sub-center clinical trial institutions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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22 Statement of Investigators  
Hereby I agree to: 
1. The clinical trial shall be carried out in strict accordance with the declaration of Helsinki, the 
current regulations of China and the requirements of the trial protocol. 
2. All required data shall be recorded in the Case Report Form (CRF) accurately and the 
clinical trial report shall be completed on time. 
3. The investigational medical device is only used in this clinical trial. During the clinical trial, 
the reception and use of the investigational medical device shall be recorded completely and 
accurately, and the record shall be kept. 
4. The sponsor is allowed to authorize or dispatch monitors, verifier, and regulatory authorities 
to monitor, supervise, and inspect the clinical trial. 
5. The terms of the clinical trial contract/agreement signed by all parties shall be strictly 
performed. 
I have read the clinical trial protocol, including the above statement, and I agree with all of the 
above. 

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Comments of the sponsor 
                              
  Signature (Seal) 
 __ __,__(month/day/year) 
 
Comments of investigators 
 
  Signature  
__ __,__(month/day/year) 
 
Comments of medical devices clinical trial institutions 
 
Signature (Seal) 
__ __,__(month/day/year)