A Clinical Study to Evaluate the Safety and Efficacy of Biologic Hollow Bone Screws
Phase: NA
Conditions: Fracture Fixation, Internal
Sponsor: FengYafei

Protocol Number: XG2114
Study Protocol
A Clinical Study to Evaluate the Safety and Efficacy
of Biologic Hollow Bone Screws
Name of Experimental Medical Device: Biologic Hollow Bone Screws
Clinical Trial Institution: The First Affiliated Hospital of PLAAir Force
Medical University
The Sponsor: Jiangxi Sike Biotechnology, China
Collaborative
Research
Organization:
Nanjing
Sigma
Medical
Technology Co., LTD
NCT Number:
Document Date: January 21, 2024

Experimental Design
1. Object
To evaluate the safety and efficacy of biologic hollow bone screws
for the fixation of fractures in knee joint and ankle joint.
2. Experimental Method
According to the Guiding Principles for Clinical Trial Design of
Medical Devices, a prospective, multicenter, randomized, single-blind,
parallel-controlled clinical trial was designed, and the comparison type
was non-inferior design.
Randomization Method: Subjects will be enrolled in this clinical
trial after signing informed consent and meeting the inclusion criteria but
not the exclusion criteria. The sample size and block length were set
using the system generation or a seed number specified by the randomizer.
The random number table required for the test was generated by the
PROC PLAN process, and the random number table was introduced into
the random system. According to the random system grouping, the
subjects were randomly assigned to the experimental group or the control
group, and the ratio of the experimental group and the control group was
1:1.
Masking (Single):
The researchers can visually distinguish the
experiment products and the control products, so the researchers cannot
be blinded and the participants were blinded.

Non-Inferior Design: The control product is a marketed device
whose efficacy/safety has been recognized, so the non-inferior design is
used. If the difference in efficacy/safety between the test device and the
control device is less than the pre-set non-inferiority threshold, the
difference is within the clinically acceptable range.
Selection of Reference Products: At present, there is no biological
bone hollow screw with the same principle and material in China.
According to the Guiding Principles for Clinical Trial Design of Medical
Devices, priority should be given to commercially available similar
products whose efficacy and safety have been clinically recognized when
selecting positive controls. And if reasonable reasons cannot be used for
similar products already on the market, a product as similar as possible
can be used as a positive control. Therefore, the absorbable screw (Inion
Freedom Screw) developed by Inion Oy, Finland, was selected as the
control product in this clinical trial.
3. Measures to Reduce and Avoid Bias
Investigator Training: Before the start of the clinical trial, the
supervisor and the principal investigator of each trial center should train
the investigators on the trial protocol and product use, so that the
investigators can understand and master the trial products, trial protocol
and process.
Clinical Trial Monitoring: The sponsor will appoint an auditor to

conduct regular on-site monitoring visits to the trial hospital to ensure
that all aspects of the study protocol are strictly adhered to, and the CRF
will be checked to ensure that the content is consistent with the original
data.
4. The Diagnosis and Treatment Methods of Experimental and
Control Medical Devices
4.1 Instructions for the Installation and Use of Experimental Devices
According to the specific conditions of each patient, the selection of
the appropriate model and size of the implant is an important factor
affecting the success rate of surgery. After implantation, the implant will
be in a repetitive stress environment for a long time, so attention must be
paid to patient selection, proper placement of the implant, postoperative
care and functional rehabilitation to minimize the stress on the implant,
otherwise such stress may lead to material fatigue and subsequent fracture,
bending or loosening of the implant before bone healing is achieved. This
can cause damage or require early removal of the implant.
4.2 Before Surgery
(1) Only those patients who meet the indication criteria should be
selected.
(2) The condition described in the contraindications section above should
be avoided.
(3) In the process of transportation and storage, avoid collision, scratches

or other forms of damage to the implant. Special care should be taken to
make the storage environment of the implant.
(4) The surgeon should be familiar with the use of this product and its
supporting instruments before use, and confirm that they are ready before
the operation.
(5) The type of implant that should be used in each surgical patient and
the approximate size range should be determined before the operation
begins. A sufficient number of implants of various sizes should be
prepared for surgery, including those larger and smaller than expected.
(6) Unless packaged in sterile form, all instruments should be cleaned and
sterilized prior to use.
4.3 During Surgery
(1) For Easy and Safe Screw Insertion:
A. The fracture site should be anatomic reduction or functional
reduction. The 1.2mm Kirchner needle should be drilled to the required
depth, and the nail path should be established along the Kirchner needle
using a hollow drill.
B. Insert the appropriate size tap along the Kirschner needle to form
the thread path. The size is consistent with the intended screw length.
Screw in to the same depth as the corresponding screw length. Screw into
the appropriate depth, counterclockwise out of the tap.
C. Select the appropriate size of the bio-type bone hollow screw and

press the screw head into the tail of the screw to ensure that the whole
screw can be picked up. Screw along the Kirschner needle until complete
implantation into the bone. The screw and screw are kept parallel to the
direction of the bone.
(2) Ensure aseptic operation during the surgery.
(3) Peripheral nerves and blood vessels should be protected during
operation.
(4) Breakage, slip or misuse of an instrument or implant during
implantation may result in injury to the patient or the surgery.
(5) For more detailed surgical instructions, please refer to the appropriate
surgical technical literature.
4.4 After Surgery
(1) The physician should provide the patient with a detailed description of
the
limitations
of
the
product.
Patients
should
be
warned
that
complications such as bending, loosening or breaking of the implant may
be caused by excessive weight bearing, excessive muscle activity or
sudden impact on the surgical site. Patients should be told how to limit
and control physical activity and advised to avoid strenuous exercise and
excessive weight bearing.
(2) During the healing stage of the fracture, the physician should advise
the patient not to smoke or drink too much alcohol.
(3) It is very important to confirm whether bone healing occurs after the

operation by X-ray. Bone non-union or delayed healing during the
treatment stage will cause the implant to be subjected to repeated stress
for a long time, which may fatigue the product and eventually bend,
loosen or fracture. Therefore, if non-healing occurs or if the implant is
loose, bent or broken, the implant should be adjusted or removed when
serious damage is imminent.
(4) Any removed implants should be properly disposed of to ensure that
the product will not be used in other surgeries.
4.5 Control Instrument Operation Methods
The operation was carried out by professional doctors participating
in this clinical trial according to the instructions.
4.6 Product Information
Items
Experimental Device
Control Device
Name
Biologic Hollow Bone Screws
Inion Freedom Screws
Type
SL30, SL32, SL34, SL36, SL38, SL40,
SL42, SL44, SL46, SL48, SL50
Diameter :3.5mm/4.5mm
Type: Hollow screw
Main Components
The product is made of silk fibroin
protein, and the degradation products
are amino acids and peptides, which
are harmless to human body. The
structure includes head thread, tail
thread, rod part and hollow hole.
The
screw
is
a
double-headed
compression
screw
to
achieve
compression fixation at both ends of
the fracture. It is hollow structure,
which is not only easy to guide needle
through, but also conducive to bone
trabecular growth.
Co60 irradiation
sterilization package.
The
product
consists
of
an
absorbable screw (L-lactic-D mixed
with L-lactic acid copolymer) and a
metal
adapter
(auxiliary
screw
screwing without contact with the
human
body).
Made
of
316
stainless steel according to ASTM
F899
standard.
Sterilized
packaging.

Application
Used for fixation of fractures of the
knee joint and ankle joint
Used in conjunction with suitable
auxiliary fixation, such as a strong
fixation implant, cast, or brace,
intended for reduction of a fracture
during fracture healing Maintain.
Source
Jiangxi Sike Biotechnology Co., LTD
Inion Oy Company, Finland.
Registration
Number
NA
National
Medical
Device
Registration: 20153130029
5. Subject Selection
5.1 Inclusion Criteria
(1) Aged 18-75 years old (inclusive), both sexes;
(2) Patients with knee and ankle fractures requiring internal fixation
confirmed by imaging examination;
(3) Voluntary participation in the clinical trial and signing of the informed
consent.
5.2 Exclusion Criteria
(1) The following conditions exist at the fracture site: infection,
osteofascial compartment syndrome, osteitis, pathological fracture, open
fracture, severe tissue or vascular and nerve injury, or insufficient bone
mass of the affected limb affecting screw implantation, etc.
(2) Abnormal liver and kidney function with clinical significance (ALT,
AST 2 times the upper limit of normal value and Cr 2 times the upper
limit of normal value);
(3) Abnormal coagulation function with clinical significance (APTT > 2

times the upper limit of normal value);
(4) Patients with difficult-to-control diabetes (any blood glucose >
11.1mmol/L or glycosylated hemoglobin > 9%);
(5) Past allergies to silk protein materials;
(6) Mental illness;
(7) Patients who cannot guarantee to quit smoking during the fracture
healing period;
(8) Pregnant or lactating women or women of childbearing age who plan
to get pregnant within 6 months;
(9) Those who have participated in other pre-clinical trials within 1
month before the trial;
(10) Those who are considered inappropriate to participate in the clinical
trial.
5.3 Remove Criteria
(1) No devices were used after enrollment.
(2) Violation of inclusion or exclusion criteria.
5.4 Drop-out Criteria
All subjects who signed informed consent and were screened for
inclusion in the trial, regardless of when and for any reason, were
drop-out cases, including:
(1) The subject requested to withdraw from the clinical trial.
(2) Adverse events or serious adverse events (SAE) occurred, which

prevented the subject from continuing to participate in the trial.
(3) The subjects had poor compliance or lost follow-up, and failed to
follow up according to the trial protocol.
(4) The investigator considers it medically necessary to suspend the
subject test.
5.5 Criteria and Procedures for Trial Termination
(1) Major errors or deviations in the clinical trial protocol are found in the
trial, making it difficult to evaluate the safety and effectiveness of the test
products.
(2) The sponsor (e.g., for financial reasons, administrative reasons, etc.)
requested termination of the trial.
(3) The administrative authority revokes the trial.
In case of the above situation, the sponsor shall promptly notify the
researchers, the medical device clinical trial institutions and the ethics
Committee. For subjects who have been treated with experimental
devices, the sponsor shall fulfill its responsibilities to the subjects during
the trial in accordance with the contents of the signed informed consent.
5.6 Group Entry Time
After signing the informed consent form, meeting the inclusion
criteria and not meeting the exclusion criteria, the time when the subject
underwent randomization was the enrollment time.
5.7 Expected Duration of Participation for Each Subject

According to the Guiding Principles for the Technical Review of
Product Registration of Metal Intramedullary Nail System and the
Guiding Principles for the Technical Review of Registration of calcium
phosphorus/Silicon bone filling Materials, the clinical healing time of
periarticular fractures of limbs is about 24 weeks, and the tissue reaction
of degradable implants should be followed up until the tissue reaction of
the products reaches a stable state after implantation. According to the
literature search of controlled products, absorbable screws can reach a
stable state about 12 months after implantation. In order to fully observe
the clinical safety of the product, the participation time of each subject
will be 18 months after surgery, so the expected participation time of each
subject is about 18 months.
5.8 The Expected Overall Duration of Clinical Trials and the Reasons
for Determination
The overall duration of the clinical trial includes the ethical approval
of all clinical trial institutions and the modification of opinions after the
ethical review, the signing time of the clinical trial agreement, the filing
time of the clinical trial, the start of the clinical trial, the enrollment time
and the examination time of the subjects, the collection time of clinical
trial data, the statistics time and the writing time of the summary report.
Combined with the number of cases to be completed in this study, the
number of cases in each research center and other factors, the final

estimated time to complete this clinical trial is about 18-22 months.
5.9 Number of Subjects Required for Clinical Trials
A total of 160 subjects were planned to be included, and 80 subjects
in the experimental group and the control group respectively. The trials
were conducted in 6 medical institutions qualified to carry out clinical
trials of medical devices, and were distributed according to the capacity
of the medical institutions to bear the number of subjects and the
principles of statistics.
6 Effectiveness Evaluation
6.1 Validity Parameter
6.1.1 Primary Outcome: Clinical fracture healing rate at 24 weeks after
surgery
6.1.2 Secondary Index:
(1) Clinical fracture healing rate at 12, 48 and 72 weeks after surgery
(2) Pain score
(3) Joint function score
(4) Device performance index
6.2 Description of Validity Parameters
6.2.1 Main Efficacy Evaluation Index: Clinical fracture healing rate at 24
weeks after surgery
Evaluation Criteria:
(1) No local tenderness and longitudinal tapping pain, no local

abnormal activity.
(2) The X-ray shows a continuous callus or trabecular bone across the
fracture line, which has been blurred.
Note: If both of the above two points are satisfied, it is considered
healed; otherwise, it is not healed.
Healing rate = (Healing cases/Total cases) × 100%
Evaluation Time: 24 weeks ± 4 week
6.2.2 Secondary Efficacy Evaluation Index
(1) Evaluation criteria for clinical fracture healing rate at 12, 48 and 72
weeks after surgery:
A. No local tenderness and longitudinal tapping pain, no local
abnormal activity.
B. The X-ray shows a continuous callus or trabecular bone across the
fracture line, which has been blurred.
Note: If both of the above two points are satisfied, it is considered
healed; otherwise, it is not healed.
Healing rate =(Healing cases/Total cases) × 100%
Evaluation time: 12 weeks ± 1 week, 48 weeks ± 4 weeks, 72 weeks ±
4 weeks.
(2) Pain score
Evaluation Method: Visual Analog Scale (VAS)
Evaluation Criteria:

A. A score of 0 represents no pain;
B. A score of 1-3 means mild pain, tolerable;
C. A score of 4-6 indicates moderate pain that affects sleep and is
tolerable;
D. A score of 7-10 indicates severe pain, unbearable pain, affecting
appetite and sleep.
Evaluation Time: Screening period, within 1 week after surgery (≦7
days), 6 weeks after surgery ± 1 week, 12 weeks after surgery ± 1 week,
24 weeks after surgery ± 4 weeks, 48 weeks after surgery ± 4 weeks after
surgery, 72 weeks after surgery ± 4 weeks.
(3) Joint function score
Evaluation Method: AKS knee function rating scale and Mazur
ankle function rating scale were used to evaluate the knee function.
Evaluation Time: 6 weeks after surgery ± 1 week, 12 weeks after
surgery ± 1 week, 24 weeks after surgery ± 4 weeks, 48 weeks after
surgery ± 4 weeks after surgery, 72 weeks after surgery ± 4 weeks.
(4) Device performance index
Evaluation project
Result
Whether the aseptic packaging is
complete
□Y □N
Whether
the
device
label
instructions are clear, complete, and
□Y □N

easy to identify
Whether the supporting equipment
is suitable
□Y □N
Whether the device is easy to
implant
□Y □N
Evaluation Time: Before surgery
7. Safety Evaluation Methods
7.1 Security Parameters
Vital signs, laboratory tests, adverse events occurring during clinical
trials,
7.2 Description of Security Parameters
7.2.1 Vital Signs: Body temperature, respiration, heart rate, blood
pressure;
Recording Time: Screening period, before surgery, during surgery,
within 1 week after surgery (≦7 days), 6 weeks after surgery ± 1 week,
12 weeks after surgery ± 1 week, 24 weeks after surgery ± 4 weeks, 48
weeks after surgery ± 4 weeks after surgery, 72 weeks after surgery ± 4
weeks.
7.2.2 Laboratory Examination: Coagulation function, blood routine, urine
routine, blood biochemistry;
Recording Time: Screening period, within 1 week after surgery (≦7

days), 24 weeks after surgery ± 4 weeks, 48 weeks after surgery ± 4
weeks after surgery, 72 weeks after surgery ± 4 weeks.
7.2.3 Adverse Events Occurred During Clinical Trials
Recording Time: Before surgery, 1 week after operation (≦7 days),
6 weeks after surgery ± 1 week, 12 weeks after surgery ± 1 week, 24
weeks after surgery ± 4 weeks, 48 weeks after surgery ± 4 weeks after
surgery, 72 weeks after surgery ± 4 weeks.

Trial Procedure
2.1 Screening Period (V0 period: -7-0 days)
Informed consent must be signed prior to any trial-related procedure,
after which subjects are assigned a unique screening number that remains
unchanged throughout the trial. If the subject is undergoing elective
surgery, it is at the discretion of the investigator whether to re-examine
the subject if the preoperative examination exceeds the acceptable time
range.
(1) Sign informed consent;
(2) Demographic data: gender, age, height, weight;
(3) Complete medical history: previous disease history within 3 months
before signing the informed consent, drug use history, smoking history,
drinking history, surgical history and allergy history within 1 month;
(4) Vital signs: body temperature, respiration, heart rate, blood
pressure;
(5) Blood pregnancy test: only applicable to women of childbearing
age;
(6) Bone mineral density examination (test site);
(7) Blood glucose test: including blood glucose and glycated
hemoglobin, only for diabetic patients;
(8) Coagulation function test: prothrombin time (PT), activated partial
thromboplastin (APTT), fibrinogen (FIB), thrombin time (TT);

(9) Blood routine: hemoglobin (HB), red blood cell count (RBC), white
blood cell count (WBC), platelet count (PLT), hematocrit (Hct);
(10) Urine routine: urinary white blood cells (WBC), urinary protein
(PRO), urinary red blood cells (RBC), urinary glucose (GLU);
(11) Blood biochemistry: creatinine (Cr), Urea nitrogen (BUN) / Urea,
alanine aminotransferase (ALT), aspartate aminotransferase (AST);
(12) C-reactive protein;
(13) Infectious disease examination: HBSAg, HBsAb, HBeAg, HBeAb,
HBcAb, HCV-rna/ HCV-antibody, syphilis TPPA, HIV antibody;
(14) X-ray examination;
(15) Determine the inclusion and exclusion criteria;
(16) VAS score;
(17) Recording device defects;
(18) Record drug combination.
2.2 Day of Surgery (Stage V1: Day 0)
(1) Vital signs: body temperature, respiration, heart rate, blood pressure;
(2) Random grouping;
(3) Record surgical information;
(4) Instrument performance index;
(5) Recording device defects;
(6) Record adverse events;
(7) Records of combined drug use (except glucose, normal saline and

narcotic drugs);
2.3 Follow-up Period (Phase V2: Within 1 week after surgery)
(1) Vital signs: body temperature, respiration, heart rate, blood
pressure;
(2) Blood routine: hemoglobin (HB), red blood cell count (RBC),
autologous cell count (WBC), platelet count (PLT), hematocrit (Hct);
(3) Urine routine: urinary white blood cells (WBC), urinary protein
(PRO), urinary red blood cells (RBC), urinary glucose (GLU);
(4) Blood biochemistry: creatinine (Cr), Urea nitrogen (BUN) / Urea,
alanine aminotransferase (ALT), aspartate aminotransferase (AST);
(5) X-ray examination;
(6) CT (3D reconstruction);
(7) MRI examination;
(8) VAS score;
(9) Recording device defects;
(10) Record adverse events;
(11) Record drug combinations (except glucose, normal saline and
narcotic drugs);
2.4 Follow-up period (Stage V3: 6 weeks after surgery±1 week)
(1) Vital signs: body temperature, respiration, heart rate, blood pressure
(2) X-ray examination;
(3) Physical examination;

(4) Joint function score;
(5) VAS evaluation;
(6) Recording device defects;
(7) Record adverse events
(8) Record drug combinations (except glucose, normal saline and
narcotic drugs)
2.5 Follow-up Period (V4 period: 12 weeks after surgery±1 week)
(1) Vital signs: body temperature, respiration, heart rate, blood
pressure;
(2) X-ray examination;
(3) Physical examination;
(4) Joint function score;
(5) VAS evaluation;
(6) Recording device defects;
(7) Record adverse events,
(8) Records of drug combinations (except glucose, normal saline and
narcotic drugs)
2.6 Follow-up Period (V5: 24 weeks after surgery±4 weeks)
(1) Vital signs: body temperature, respiration, heart rate, blood
pressure;
(2) Blood routine: hemoglobin (HB), red blood cell count (RBC),
autologous cell count (WBC), platelet count (PLT), hematocrit (Hct)

(3) Urine routine: urinary white blood cells (WBC), urinary protein
(PRO), urinary red blood cells (RBC), urinary glucose (GLU)
(4) Blood biochemistry: creatinine (Cr), Urea nitrogen (BUN) / Urea,
alanine aminotransferase (ALT), aspartate aminotransferase (AST);
(5) X-ray examination;
(6) CT (3D reconstruction)
(7) MRI examination;
(8) Physical examination;
(9) Joint function score:
(10) VAS score;
(11) Recording device defects:
(12) Record adverse events;
(13) Record drug combinations (except glucose, normal saline and
narcotic drugs)
2.7 Follow-up Period (Phase V6: 48 weeks after surgery±4 weeks)
(1) Vital signs: body temperature, respiration, heart rate, blood
pressure;
(2) Blood routine: hemoglobin (HB), red blood cell count (RBC), white
blood cell count (WBC), platelet count (PLT), hematocrit (Hct);
(3) Urine routine: urinary white blood cells (WBC), urinary protein
(PRO), urinary red blood cells (RBC), urinary glucose (GLU);
(4) Blood biochemistry: creatinine (Cr), Urea nitrogen (BUN) / Urea,

alanine aminotransferase (ALT), aspartate aminotransferase (AST);
(5) X-ray examination;
(6) MRI examination;
(7) Physical examination;
(8) Joint function score;
(9) VAS score;
(10) Recording device defects;
(11) Record adverse events;
(12) Record drug combinations (except glucose, normal saline and
narcotic drugs);
2.8 Follow-up Period (Stage V7: 72 weeks after surgery± 4 weeks)
(1) Vital signs: body temperature, respiration, heart rate, blood
pressure;
(2) Blood routine: hemoglobin (HB), red blood cell count (RBC), white
blood cell count (WBC), platelet count (PLT), hematocrit (Hct);
(3) Urine routine: urine white blood cell (WBC), urine egg (PRO),
urine red blood cell (RBC), urine glucose (GLU);
(4) Blood biochemistry: creatinine (Cr), Urea nitrogen (BUN) / Urea,
alanine aminotransferase (ALT), aspartate aminotransferase (AST);
(5) X-ray examination;
(6) MRI examination;
(7) Physical examination;

(8) Joint function score;
(9) VAS score;
(10) Recording device defects;
(11) Record adverse events;
(12) Record drug combinations (except glucose, normal saline and
narcotic drugs);

Specifications for Use of Devices
(1) All investigators performing the device operation in this clinical
trial must be GCP certified, trained and skilled physicians.
(2) For unified handover of medical devices for testing, there should be
a special person to check and process records. After the handover of the
product, the medical device clinical trial management department.
(3) Each research unit shall establish a strict test instrument
management system. For the special purpose of the device administrator
form registration.
(4) The sponsor shall refer to the provisions of the State Drug
Administration on the management of medical device instructions and
labels, the experimental medical devices for appropriate identification,
and marked "experimental" .
(5) The records of experimental medical devices including production
date, product batch number and other production-related records and
product quality and stability related inspection records, Records of
transportation
and
delivery
of
medical
devices
to
clinical
trial
management departments for use, as well as post-trial recovery and
disposal dates, etc.
(6) The use of investigational medical devices is the responsibility of
the clinical trial institution and the investigator, and the investigator shall
ensure that all investigational medical devices are used only for the

subjects of the clinical trial, and the investigator shall not transfer the
investigational medical devices to any non-participants in the clinical trial.
Before use, sterilization should be carried out according to the
requirements and instructions.
Statistical Analysis
1. Statistical Design
A
prospective,
multicenter,
randomized,
single-blind,
parallel-controlled clinical trial was conducted. The comparison type was
non-inferiority design.
2. Analytical Methods
95% confidence interval method was used for the main efficacy
indicators, and bilateral tests were used for all statistical tests, and P≤0.05
was considered to be statistically significant.
The description of quantitative indicators will calculate the mean,
standard deviation, median, minimum, maximum. The classification
index is described by the number of cases and percentage of each type.
Statistical analysis was performed using SAS 9.4 software.

Data Management
(1) Data Recording and Transfer
Electronic Case report Form (eCRF): The data manager designed
and constructed according to the experimental scheme, and set logical
verification according to the data verification plan (DVP). After passing
the test and obtaining the sponsor's approval, the ECRF will be released
for use.
Data entry: The eCRF data comes from the original records, and the
data entry personnel fill in the instructions according to the eCRF, and
enter the subject's visit data into the EDC in time.
(2) Data Processing and Record Preservation
Source data on-site verification (SDV): The inspector can query
the consistency of eCRF data and source data.
Data questions and answers: Questions come from EDC logical
verification system questions, inspectors, data administrators and other
manual questions, researchers need to answer questions in time. The data
manager and the monitor give the question approval and issue the
question again if necessary until the data is "cleared".
Researcher signature: After data entry is completed and passed
through the SDV, the researcher will conduct an electronic signature
review and confirmation.
If the data is modified after the signature, you need to re-sign it.

Adverse events were coded using the MedDRA (21.0 or above)
dictionary, and drug combinations were classified by WHO ATC.
(3) Database Locking
Database
locking:
After
the
principal
investigator,
sponsor,
statistical analyst, and data manager jointly sign the database locking
record, the data manager performs the database locking.
Database
submission:
Data
manager
submits
database
to
statisticians, eCRF archive: eCRF generated PDF electronic document for
each subject is saved, data management report: written by data manager,
EDC shutdown: After statistical analysis is complete, the data
administrator closes the database.

Feasibility Analysis
(1) Analysis of the Possibility of Success
A. The test products have passed strict inspection, and the test
results are qualified.
B. After training, the researchers are proficient in the use of the test
equipment and operate in strict accordance with the plan.
C. Participants were selected according to strict inclusion/exclusion
criteria.
(2) Possibility Analysis of Failure
This test routine does not fail, which may result in failure if :
A. Enrolled subjects who do not meet the inclusion criteria.
B. Failed to test relevant laboratory indicators according to the
scheme.
C. The operator is not skilled in operation and makes mistakes in
use.

Quality Control of Clinical Trials
(1) Training of Researchers
Before the start of clinical trial, the experimental institution or
sponsor should conduct product training, program training and clinical
trial process training according to the investigator's manual, specification
and clinical protocol.
(2) Measures to Improve Subjects' Compliance
Researchers should carefully implement informed consent so that subjects
fully understand the requirements of the experiment and cooperate with
the experiment.
(3) Supervision of Clinical trials
An auditor appointed by the sponsor conducts regular site visits to the
trial hospital to ensure that all aspects of the study protocol are strictly
adhered to and the CRF is checked to ensure consistency with the original
data.

Ethical Protection and Informed Consent in Clinical
Trials
(I) Ethical Considerations
Clinical trials must be conducted in accordance with the Declaration
of Helsinki and relevant clinical trial research norms and regulations in
China. Before the start of the trial, the clinical trial can be carried out only
after the trial protocol is approved by the ethics committee of the clinical
trial unit.
Before each subject is enrolled in this study, it is the investigator's
responsibility to provide him or his legal representative with a complete
and comprehensive written description of the purpose, procedures, and
possible risks of this study. Subjects should be made aware of their right
to withdraw from the study at any time. A written informed consent must
be given to each subject before enrollment, and the investigator is
responsible for ensuring that each subject obtains informed consent
before entering the study. Informed consent should be kept as clinical trial
documentation for future reference.
(2) Informed Consent Process and Informed Consent
Before
the
participants
participate
in
the
clinical
trial,
the
investigator shall fully explain the details of the clinical trial to the
participants or their family members, guardians and legal representatives,
including known and foreseeable risks and possible adverse events. After

full and detailed explanation, the subject or his legal representative shall
sign the name and date on the Informed consent, and the researcher
performing the informed consent shall also sign the name and date on the
informed consent, and the informed consent shall be signed before the
subject accepts any test procedure, and any amendment shall be
accompanied by a written explanation of the reason behind the Informed
Consent.
The Informed consent should indicate the date of preparation or the
date of the revised version. This information will help confirm that the
correct version is being used. If the Informed Consent Form is revised
during the experiment, the revised Informed Consent form shall be
reviewed and approved by the Ethics Committee again before execution.
After the revised Informed Consent is approved and sent to the clinical
trial institution for record, all subjects who have not completed the trial
process must sign the newly revised Informed Consent.

Requirements for Reporting Adverse Events and
Device Defects
(1) Definition and Reporting of Adverse Events
A. Definition of adverse events
Adverse events refer to adverse medical events that occur during
clinical trials of medical devices, whether or not they are related to the
experimental medical devices. Adverse events were recorded from device
use.
B. Severity determination of adverse events
Observe the process, extent, disposal and outcome of adverse events
in detail, and fill in the adverse event report form. Adverse events were
classified as mild, moderate, and severely mild according to the following
criteria:
Mild: Tolerable to the subject, does not affect treatment, does not
require special treatment, and has no impact on the health of the subject
Moderate: The subject is unbearable, requires special treatment, has
a direct impact on the health of the subject.
Severe: Endangering the life of the subject, causing death or
disability, requiring immediate emergency treatment.
C. Evaluation of adverse events
According to the test product is definitely relevant, very likely to be
relevant, possibly relevant, possibly irrelevant, definitely irrelevant five

levels of evaluation.
Must be relevant: the occurrence of the reaction is consistent with a
reasonable time sequence after the use of the product, consistent with the
type of reaction known to the product, the disappearance of the reaction
after discontinuation, and the reaction cannot be explained by clinical
manifestations of the disease or other causes other than the product.
It is likely to be relevant: the occurrence of the reaction is consistent
with a reasonable time sequence after the use of the product, consistent
with the type of reaction known to the product, the reaction improves
significantly after discontinuation, and the reaction cannot be explained
by clinical manifestations of the disease or other causes other than the
product.
May be relevant: The occurrence of the reaction is consistent with a
reasonable time sequence after the use of the product, consistent with the
type of reaction known to the product, the response improves after
discontinuation, and the patient's clinical status or other treatment may
cause a similar reaction.
May not be relevant: The occurrence of the reaction is not consistent
with a reasonable time sequence after the use of the product, is not
consistent with the type of reaction known to the product, the reaction
improves after discontinuation, the patient's clinical status or other
treatment may cause a similar reaction, and may be mitigated with

disease improvement or other measures.
Certainly not: The occurrence of the reaction does not conform to a
reasonable time sequence after the use of the product, does not conform
to the type of reaction known to the product, the reaction does not
improve after discontinuation, the patient's clinical status or other
treatment may cause a similar reaction, the disease status improves or the
response disappears after discontinuation of other treatment.
(2) Device Defect
Device defect refers to the unreasonable risks that may endanger
human health and life safety under normal use of medical devices in the
course of clinical trials, such as label errors, quality problems, failures,
etc. In the course of this clinical trial, if the use of devices fails due to
device defects, the investigator shall conduct routine treatment according
to clinical needs. The investigator should document all discovered device
defects that occur during clinical trials.
(3) Definition of Serious Adverse Events
A. Definition of serious adverse events
Serious adverse events refer to those that occur during clinical trials
of medical devices resulting in death or serious deterioration of health.
Including fatal diseases or injuries, permanent defects in body structure or
body function, the need for hospitalization or prolonged hospitalization,
the need to take medical measures to avoid permanent defects in body

structure or body function: events leading to fetal distress, fetal death or
congenital
abnormalities,
birth
defects,
etc.,
during
screening
or
follow-up, Prospective or elective surgery performed by subjects was not
recorded as a serious adverse event.
B. Serious adverse event reporting process
If a serious adverse event occurs in a clinical trial, the investigator
shall immediately take appropriate treatment measures for the subject;
meanwhile, the investigator shall report the serious adverse event to the
sponsor, the management department of the medical device clinical trial
institution, and the ethics committee within 24 hours after learning about
it; Serious adverse events were followed up in accordance with the
provisions of the clinical trial protocol, and serious adverse event
follow-up reports were submitted.
Direct Access to Source Data and Files
Clinical trial institutions and investigators should allow trial-related
monitoring, verification, ethics committee, and regulatory inspections
with direct access to source data/documents.

Confidentiality Principle
This trial protocol is confidential and is intended to be provided to
medical experts, researchers participating in the trial and other staff
involved in the trial, as well as relevant business entrusting institutions
such as medical institutions, ethics committees and contract research
organizations undertaking the trial. Except to explain the situation to the
subject, no content of this test protocol shall be disclosed or disclosed to
any third party without the prior written consent of the sponsor. In
addition, the written consent of the sponsor is required for the partial or
full results of this clinical trial to be published externally to the society,
journal, etc.