Medical device clinical trial protocol

Scheme number: YNCXQ-20240820

A prospective, multicenter, randomized, parallel-controlled, superiority clinical trial plan for the safety and efficacy of single-use gel patch formers for clinical use

Name of the test medical device: Disposable gel patch former

Model specification: YN-PAT 35

Class III medical devices subject to clinical trial approval Yes□ No R

Solution version number and date: V 4.0 202 5-03-17

Clinical trial institution: Run Shaw Hospital Affiliated to Zhejiang University School of Medicine

Principal investigator: Wang Qiang

Clinical trial team leader unit/coordinating investigator (for multicenter clinical trials): Wang Qiang

Sponsor: Hangzhou Yuannang Biotechnology Co., Ltd

Signature Page - Principal Investigator

Clinical trial title: Prospective, multicenter, randomized, parallel-controlled, superiority clinical trial clinical trial protocol for the safety and efficacy of single-use gel patch formers for clinical use

Solution version number and date: V 4.0 202January 2, 202

Research Center Name: Run Shaw Hospital, Zhejiang University School of Medicine

Research center number: 01

I am the signatory of the following and I am responsible for presiding over this clinical trial at our center. I will perform my duties as a researcher diligently in accordance with GCP regulations. I confirm that I understand and will follow this clinical trial protocol, any approved trial protocol amendments, our country GCP, ICH-GCP and all applicable national laws and regulations and drug regulatory authorities require this clinical trial to be carried out. I will be responsible for making medical decisions related to clinical trials and ensuring that subjects receive appropriate medical management in the event of adverse events during the trial. I guarantee that the data will be recorded truthfully, accurately, completely, timely, and legally. I will accept the supervision or inspection of the supervisor or inspector appointed by the sponsor and the inspection and inspection by the drug administration department to ensure that the quality of the clinical trial meets the requirements.

Signature: Date:

Confidentiality Statement

All information contained in this protocol belongs to Hangzhou Yuannang Biotechnology Co., Ltd., so it is only provided to relevant medical institutions such as researchers, collaborating investigators, ethics committees, and regulatory authorities. Without the written approval of Hangzhou Yuansang Biotechnology Co., Ltd., it is strictly forbidden to inform any information to third parties unrelated to this study, except for the necessary explanation when signing the informed consent form with subjects who may participate in this study.

1. Applicant information

(1) Name of the applicant

Hangzhou Yuansang Biotechnology Co., Ltd

(2) The address of the applicant

Room 803, 8th Floor, Corridor of Hangzhou Bay Information Port Building 2, No. 371 Xingxing Road, Xiaoshan District, Hangzhou

(3) Contact information of the applicant

Contact: Yang Dan

Contact number: 0571-88313603

2. Information on clinical trial institutions and principal investigators

If the clinical trial institution and investigator change during the trial, each change can be updated without the formal revision of the plan, and the version number and version date of the protocol can be saved by the lead unit, and the sponsor will keep an updated list and provide it when needed. A final list of all clinical trial sites and investigators is provided in the final clinical summary report.

Table 1 List of clinical trial institutions and investigators

3. Background information of clinical trials

(1) R&D background

Enhancing wound tissue healing has been the goal of doctors for thousands of years. As China accelerates into an aging society, the trauma care market is growing rapidly. Many patients, especially the elderly with underlying diseases, are not repaired in time after injury, and are prone to develop into chronic wounds and face risks such as gangrene and amputation. Treatment of refractory wounds is an ongoing medical problem, with tens of millions of patients suffering from refractory wounds in China. Taking diabetic foot ulcer (DFU) as an example, its treatment cost accounts for 25-50% of the total cost of diabetes treatment. Among them, 5%-8% of DFU patients require amputation in the first year, and about 45%-55% of patients die 5 years after amputation. Refractory wounds have become a health problem with a large base of patients and urgently need to be solved.

At present, the treatment methods of refractory wounds mainly include necrotic tissue debridement, infection control, revascularization, local decompression and comorbidity treatment. However, these treatment strategies often need to be performed simultaneously and lead to significant treatment costs and complexities. In order to improve the healing of intractable wound tissue, some international companies have developed many types of new technologies and regenerative dressing products, including growth factor delivery, gene therapy, etc. However, due to the complexity of refractory wounds, different individuals have different biochemical characteristics, and it is difficult to achieve ideal wound healing by supplementing a single growth factor or targeting only a single gene, and some advanced treatments have unknown risks. Therefore, these treatments have not been officially approved in China. As a regenerative repair treatment, autologous PRP has been widely used in postoperative repair of fractures in China. There are a large number of clinical studies at home and abroad that confirm that autologous PRP can effectively promote wound healing. As a convenient, painless, low-risk treatment method, rich in a large number of growth factors, the therapeutic effect is remarkable, and autologous PRP treatment is widely accepted by patients.

Although the wound healing effect is excellent, due to the diversity of clinical tissue wounds, there are no PRP products on the market that are well adapted to wound repair, so domestic autologous PRP/PRP gel is not widely used in wound treatment. Most of the PRP products currently on the market are finally made of PRP liquid, which cannot be directly applied to the treatment of tissue repair such as refractory wounds. Some products combine thrombin to make fibrinogen aggregate in PRP plasma to form PRP gels. However, naturally formed PRP gels have a loose structure and extremely high water content. There are many adverse consequences when used directly on the wound: a) Naturally formed PRP gel has a very high water content, after gauze bandaging, the water in the gel will be gradually absorbed by the gauze, and the gel will immediately shrink after water loss, which will cause a large loss of growth factors and cause gauze exudation, increasing the risk of further infection of the wound. b) Naturally formed PRP gels have a loose structure and are easily degraded. Moreover, the surface of the gel is moist and smooth, making it difficult to continue to adhere to the wound, and it is very easy to cause the gel to shift due to the patient's movement. c) From the microstructure, it is found that the pore size of the naturally formed PRP gel is larger than that of leukocytes and platelets (>9μm), so it cannot effectively realize the encapsulation of leukocytes and platelets, and is easy to be quickly lost and degraded under the washing of body fluids. It cannot play a role in promoting continuous repair. Therefore, there are still many inconveniences and problems in the treatment of refractory wounds. Therefore, there is an urgent need for a product that can improve the application of PRP in difficult-to-heal wounds to achieve a good therapeutic effect of PRP in accelerating wound tissue healing.

In view of the inconvenience of most PRP preparation products on the market for the use of difficult-to-heal wounds, the research team of Hangzhou Yuancapsu Biotechnology Co., Ltd. has developed a molder product that can prepare PRP into concentrated PRP gel patches. As a former, the product prepares loose plasma gels into higher-strength plasma gel patches without changing the chemical structure and biological properties of PRP gels through physical extrusion. The product is simple to operate and has a short preparation time. Compared with the naturally formed PRP gel, the gel patch has stronger mechanical strength, and can be sutured with sutures with wound tissue, and can be cut at will according to the shape of the wound. The formed gel patch significantly prolonged the degradation time of the gel and increased the slow-release concentration and duration of growth factors. At present, this product has been inspected by the National Medical Products Administration (NMPA) certified inspection agency and concluded to be qualified, and has applied for clinical trials in order to further evaluate the clinical safety, efficacy and operability of the device.

(2) Basic product information (including structural composition, working principle, mechanism of action, product characteristics, etc.)

1.Product features:

This product is composed of mature medical materials, with high safety and good biocompatibility.

The product is physically extrusion, and the PRP gel is squeezed into a patch form and applied to the chronic wound surface to promote wound repair.

2. Product structure composition

This product is composed of five parts: shell, core rod, rubber plug, filter membrane and deflector, ethylene oxide sterilization, disposable use.

3.The working principle and mechanism of the product

The product filters out the water in the PRP gel through physical extrusion and extrudes it into a patch shape, which enhances the mechanical strength, platelet and growth factor concentration of the PRP gel. Gel patches applied to chronic wounds can promote wound repair.

(3) Scope of application and relevant information

1.Indications:

The product is used by doctors in medical institutions to process platelet-rich plasma and thrombin into gel patches, which are immediately used for tissue repair in patients.

2.Contraindications

If you are allergic to rubber and other ingredients in the single-use gel patch former, it is strictly forbidden to use this product.

3.Notes:

If the packaging is found to be damaged or cracked during use or if it exceeds the expiration date, it is prohibited to use it.

The product is for one-time use and reuse is strictly prohibited.

This product needs to be operated and used by professional medical personnel in strict accordance with the instructions after relevant training and qualification.

After use, please dispose of this product as medical waste.

During the use of the product, you need to bring your own product dispensers of different specifications such as 1mL and 10mL and corresponding dispensing needles;

During the use of the product, it is necessary to prepare its own pharmaceutical thrombin;

During the use of the product, it is necessary to prepare its own disposable medical three-way valve;

During the use of the product, you need to bring your own adaptive bracket.

4. Purpose of the experiment

To investigate the safety and efficacy of the single-use gel patch former for clinical operational use.

5. Experimental design

(1) Overall design and determination basis

This clinical trial adopts a multicenter, randomized, parallel-controlled, and superiority test design, and selects clinical trial institutions in the medical device clinical trial institution filing management information system. After all subjects sign the informed consent form, their basic information is collected and randomly enrolled in the experimental group or control group to conduct clinical trials to observe the safety and efficacy of the product.

Prospective: avoid selectivity bias and recall bias caused by retrospective trials, and the results are more scientific;

Multicenter: Multicenter clinical trials can shorten the clinical trial time by using multicenter clinical trials to obtain more cases than a single center in the same time period; Since the multicenter trial was completed by different researchers in different hospitals, the conclusions were more broadly representative.

Randomization: The investigator enrolled the subjects in the experimental or control group according to the principle of randomization, ensuring that the possible confounding effects were as consistent as possible among the groups except for the treatment factors, so as to maintain the balance of the groups.

Parallel control: This clinical trial uses PRP gel, which is commonly used for the treatment of chronic wounds, as a control treatment, which has formed an expert consensus and can be compared with this method to draw scientific conclusions.

Sign first and inform before screening and enrollment: Protect the subject's right to know, and also ensure the subject's right to choose independently, and safeguard the rights and interests of the subject.

(2) Subject selection

1. Selection criteria

18-75 years old;

Patients with chronic wounds requiring debridement repair;

Wound duration> 4 weeks;

Volunteer to participate in this study and sign the informed consent form;

2. Exclusion criteria

Patients with severe thrombocytopenia and sepsis;

Patients who are allergic to rubber ingredients;

Patients who have been injected with glucocorticoids within 1 month or systemic corticosteroid therapy within 2 weeks;

Patients with malignant tumors;

Hemoglobin < 100g/L, platelet count < 100×10⁹/L ；

Mental illness, cognitive impairment, critically ill patients, minors, and pregnant women;

Those who have participated in or are participating in drug clinical trials within 3 months, or have participated in or are participating in other medical device clinical trials within 30 days;

Other conditions that the investigator deems unsuitable for participation in the study.

3. Subject withdrawal criteria and procedures

Subjects withdraw on their own

Regardless of the reason, the subject is unwilling or unable to continue the clinical trial, and the clinical trial is terminated by requesting the investigator to withdraw from the clinical trial;

Although the subjects did not explicitly propose to withdraw from the clinical trial, they no longer received treatment and examination and were lost to follow-up.

The researcher decided to withdraw

Subjects with allergic reactions or serious adverse events (SAEs) and unable to complete subsequent trials, the clinical trial should be terminated according to the investigator's judgment;

During the clinical trial, the subject has other complications and is not suitable to continue to undergo the clinical trial;

Subjects who do not meet the inclusion criteria of the trial, are wrongly selected due to meeting the exclusion criteria, and do not use the test device;

During the clinical trial, the subject has serious deviations from the protocol, such as the use of devices not specified in this protocol during the trial, or the use of combined drugs within the scope of non-specified drugs in the middle of the trial, which can no longer effectively evaluate the clinical trial results;

Poor subject compliance.

After the termination of the subject's trial, the investigator should continue to provide appropriate treatment to the subject from the perspective of protecting the rights and interests of the subject, and inform the subject in detail of the treatment and related treatment received during the trial. Data from subjects can still be used to evaluate the safety of the product. The investigator should promptly feedback the termination of the subject's trial to the sponsor.

(3) Evaluation methods

1. Effectiveness evaluation

Main evaluation indicators

The main evaluation index was the qualified rate of platelet concentration.

Evaluation methods: Platelet concentrations in PRP and gel patches prepared by the product were tested.

Anticoagulant peripheral blood (about 20mL, evenly divided into platelet-rich plasma (PRP) group and gel patch (patch) group), PThe upper layer of plasma and platelets were obtained after centrifugation of 150× g for 10 min in the RP group, and 10 mL was obtained The platelet-containing plasma was transferred to a new centrifuge tube, centrifuged at 800×g again for 5 minutes, about 3/4 of the supernatant was discarded, and the lower layer was mixed well to obtain platelet-rich plasma , the measured platelet concentration is recorded as .

The upper layer of plasma and platelets were obtained after centrifugation of 150×g for 1 0 minutes, and the platelet plasma volume and platelet concentration were measured 。 According to the product manual, platelet plasma and 1/10 volume of thrombin are mixed in a disposable gel patch former and then extruded into a gel patch. The leachate liquid was retained, and the volume of the leachate fluid and platelet concentration were measured.

Platelet concentrations in each group were measured and calculated according to the formula.

Recording time: within 3 hours after the preparation of PRP gel patches.

Analysis method: Prepare the sample according to the evaluation method and measure it, and calculate the platelet concentration in the gel patch according to the following formula.

According to the blood routine platelet concentration of the patient V1 visit, the enrichment factor N of platelets in the control group and the test group was calculated according to the following formula:

Control group: Experimental group:

If the enrichment multiple is in the range of 2-8 times, it is considered qualified.

The pass rate of platelet concentration in the two groups was calculated and the superiority test was performed.

Secondary evaluation indicators

Secondary evaluation indicator 1: Wound bacteria 3 days after surgery.

Evaluation methods: At the end of intraoperative debridement and 3 days after surgery, the investigator took the secretions from the wound site of the control group and the experimental group for bacterial culture examination.

Recording time: intraoperative (end of debridement) and 3 days postoperatively.

Analysis methods: According to the table below, the bacterial situation of the wound in the two groups was scored, and the difference analysis between the scores was performed between the two groups.

Secondary evaluation index 2: growth factor concentration.

Evaluation methods: Approximately 20mL of anticoagulant peripheral blood was collected, and it was evenly divided into PRP group and patch group. P RP group was centrifuged at 150×g for 10 minutes to obtain upper layer plasma and platelets, and the platelet-containing plasma was transferred to a new centrifuge tube. Centrifuge at 800×g again for 5 minutes, discard 3/4 of the supernatant, mix the lower layer well to obtain platelet-rich plasma, and add 1/10After the volume of thrombin is gelled, it is placed in a 50mL centrifuge tube and infused with 4 times the volume of normal saline at 37 °C for 1 hour.

Platelet-containing plasma was obtained after centrifugation of 150×g for 10 minutes, and according to the product instructions, platelet-containing plasma and 1/10 were obtained The volume of thrombin was mixed in a disposable gel patch former, then extruded into a gel patch, the patch was placed in a 50mL centrifuge tube, and 4 times the volume of normal saline was added to the 37°C extraction 1 hour. After the extraction, the gel and gel patch were removed and PDGF-BB, TGF-β 1 and IL-1β were detected with the ELISA kit Concentration of three factors.

Recording time: within 12 hours after the preparation of PRP gel and gel patch is completed.

Analysis methods: The concentration of growth factors released by PRP gel and gel patch was detected according to the evaluation method, and the difference analysis between groups was carried out.

Secondary evaluation index 3: ultimate tensile strength.

Evaluation methods: The remaining platelet-rich plasma (PRP group) and gel patch (patch group) were taken for tensile strength testing.

In the PRP group, 1.8mL of platelet-rich plasma and 1/10 volume of thrombin were added to φ35 mm round cake dishThe middle is made into glue.

The maximum tensile force that the gel can withstand is tested with a handheld tensile meter.

Recording time: within 3 hours after the preparation of PRP gel and gel patch is completed.

Analysis methods: The maximum ultimate tensile force of PRP gel and gel patch was recorded according to the evaluation method, and the difference analysis between groups was performed to verify the effectiveness of the product in enhancing the gel tensile force.

Secondary evaluation criterion 4: postoperative wound condition

Evaluation method: Three days after surgery, the investigator scored the wound of the subjects according to the "Wound Assessment Form" to evaluate the wound infection. The Wound Assessment Form is as follows:

References:

Armstrong DG., et al. Diabetic Foot Ulcers: A Review. JAMA. 2023. Jul; 3; 330(1):62-75.

Recording time: 3 days postoperatively.

Analysis method: The wound of the control group and the test group was scored according to the evaluation method at 3 days after surgery, and the difference analysis between the two groups was carried out.

Secondary evaluation indicator 5: product use performance

Evaluation method: The performance of the test instrument was evaluated by the surgical investigator after surgery, and the evaluation content was as follows:

Among the three dimensions of product performance, operation process, and preparation performance, at least one evaluation in each dimension is "yes", and at least 9 of the above 12 evaluation contents are rated as "yes", and the performance evaluation is "satisfactory". Otherwise, the performance of the use is rated as "unsatisfactory".

Recording time: The day the surgery is completed.

Analysis method: According to the evaluation method and the following formula, the satisfaction of the performance of the test instrument is counted.

Secondary evaluation indicator 6: platelet concentration

Evaluation methods: The platelet concentrations of P RP group and patch group were obtained according to the measurement and calculation results in the main evaluation indicators. Right

Recording time: within 3 hours after the preparation of PRP gel patches.

Analysis methods: The platelet concentrations of PRP group and patch group were analyzed between groups.

2. Safety evaluation

Safety evaluation index 1: Abnormal laboratory examination

Evaluation methods: Blood routine, liver function, and kidney function were reviewed 3 days after surgery, and red blood cell count (RBC), white blood cell count (WBC), neutrophil ratio (NEUT%), and hemoglobin concentration () were recorded in blood routine HGB), platelet count (PLT) test results; The results of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in liver function were recorded. The results of creatinine (CRE), urea nitrogen (BUN) or urea (UREA) tests in renal function were recorded. Record blood C-reactive protein results. If the test results are normal or abnormal but not clinically significant, the results are judged to be normal, and if the test results are abnormal and clinically significant, they are treated as abnormal results.

Recording time: 3 days postoperatively.

Analysis method: Calculate laboratory abnormalities according to the evaluation method and the following formula.

Safety evaluation index 2: vital sign examination

Evaluation methods: Basic vital signs were reviewed 3 days after surgery, and body temperature, pulse, respiration, and blood pressure were recorded.

Recording time: 3 days postoperatively.

Analysis method: According to the evaluation method, the vital signs of the experimental group and the control group were recorded 3 days after surgery, and the difference between groups was analyzed.

Safety evaluation index 3: occurrence of adverse events and serious adverse events

Evaluation methodology: Any adverse medical event during the trial, whether or not device-related, is an adverse event. Serious adverse events are determined if they occur during the course of a clinical trial that result in death or serious deterioration of health. All adverse events and serious adverse events should be determined to be related to the test device. The relationship between adverse events and serious adverse events and the test device is divided into "definitely related", "likely related", "possibly related", "possibly unrelated", "not related", and divided into adverse events, serious adverse events and device-related adverse events, Serious adverse events reflect the safety of the test device.

Expected adverse events of the test device include: device defects, wound discomfort, wound infection, etc.

Device defects: refers to whether there are functional failures such as broken device packaging and equipment damage during surgery.

Wound discomfort: refers to the occurrence of severe pain, numbness, and itching in the wound after surgery.

Wound infection: refers to whether wound infection occurs after surgery.

Note: Conditions related to clinical diagnosis and previous underlying disease (based on baseline examination or past medical history) may not be reported as adverse events if the severity and treatment do not change.

Recording time: From the time the subject is confirmed to enroll to the group 3 days after surgery.

Analysis methods: Adverse events and serious adverse events that occurred during the trial were recorded according to the evaluation method, and the incidence of adverse events and serious adverse events was calculated according to the following formula, and the difference analysis between groups was carried out.

(4) Experimental medical devices and control diagnosis and treatment methods

1. Test group

Peripheral blood was collected, and after debridement, PRP gel patches prepared by a disposable gel patch former were applied to the wound surface. The remaining blood was used for performance detection of P RP gels and gel patches.

2. Control group

Peripheral blood was collected, and after debridement, PRP gel was applied to the wound surface. The remaining blood was used for performance detection of P RP gels and gel patches.

(5) Test process

1. Test flow chart

Table 3 Test flow table

2. Experimental implementation (methods, contents, steps, etc.).

Case enrollment

Sign the informed consent form (signature and date), and record the subject's basic information, including date of birth, gender, height, weight, clinical diagnosis and past medical history, allergy history, etc. Record the results of the examination that need to be performed before enrollment. Appropriate subjects are selected according to the inclusion and exclusion criteria.

Inspection/Inspection Items

Visit 1: Screening period examination

Preoperative liver function tests: alanine aminotransferase (ALT), aspartate aminotransferase (AST).

Preoperative renal function tests: creatinine (CRE), urea nitrogen (BUN), or urea (UREA).

Preoperative blood routine tests: red blood cell count (RBC), white blood cell count (WBC), neutrophil ratio (NEUT%), lymphocyte ratio (LTMPH%), hemoglobin concentration (HGB), platelet count (PLT).

Preoperative C-reactive protein test.

Vital signs (temperature, pulse, respiration, blood pressure).

Visit 2: Chronic ulcer repair

Preoperative peripheral blood draw.

Bacterial culture of wound secretions after debridement.

Evaluation of product use performance after surgery.

Visit 3 (within 3 days after surgery):

Bacterial culture of wound secretions.

Routine blood tests: red blood cell count (RBC), white blood cell count (WBC), neutrophil ratio (NEUT%), lymphocyte ratio (LTMPH%), hemoglobin concentration (HGB), platelet count (PLT).

Liver function tests: alanine aminotransferase (ALT), aspartate aminotransferase (AST).

Renal function tests: creatinine (CRE), urea nitrogen (BUN), or urea (UREA).

Postoperative C-reactive protein examination.

Wound assessment.

Vital signs (temperature, pulse, respiration, blood pressure).

Confirm the group

This trial identifies the trial group of subjects according to the principle of randomization.

After the subjects sign the informed consent form, they will be given a screening number first, and the subject number will be given after passing the screening.

The screening number is composed of S+2-digit trial center number + 2-digit serial number, and the screening number is given according to the time of signing the informed consent form, and the serial number is less than 2When the position is increased, 0 is added forward to make up for 2 digits.

Programmed with statistical software, stratified by center, given block length, subjects were divided into experimental and control groups in a 1:1 ratio, resulting in a randomization arrangement of at least 38 subjects, and a corresponding random number table was developed.

The subject number is a four-digit number composed of the center number and the serial number, the first 2 digits are the test center number, the last 2 digits are the serial number, and if the serial number is less than 2 digits, 0 is added forward to make up for 2 digits. After the subjects are selected, the investigator confirms the subject group according to the random envelope and takes the corresponding group of devices for treatment.

Experimental procedure

On the day of surgery, about 50-6 0mL of peripheral blood is drawn from the patient's vein, and 6 0mL can be collected as much as possible.

About 20mL of peripheral blood was taken, and the control group was centrifuged at 150×g to obtain the upper layer of plasma and platelets, which were transferred to a new centrifuge tube for another 800 ×g centrifugation, discard about 3/4 of the supernatant, and mix the lower layer to obtain platelet-rich plasma. The test group performed the same first step of centrifugation to obtain platelet-containing plasma for backup. After preparation, store at 1-10°C and send to the operating room as needed. The remaining blood is used to measure platelet concentration, tension, and growth factor concentration.

The wound site is disinfected according to the requirements of routine surgery, the necrotic tissue is fully removed, and the debridement is thorough until the soft tissue with healthy bleeding is completely exposed. According to the literature report, we designed an evaluation form for debridement treatment (Table 4 "Debridement Evaluation Form"), and the researchers scored according to the table, and when the scores of the three dimensions were ≥ 4 points and the total score was ≥ 12 points, the debridement could be considered complete, and the wound surface was secreted and sent for bacterial cultureDetect.

References:

Schultz, G., et al. Wound Bed Preparation: A Systematic Approach to Wound Management. Wounds International, 2003. Mar; 11 Suppl 1:S1-28.

Falanga, V. Wound Healing and Its Impairment in the Diabetic Foot. The Lancet, 2005. Nov 12; 366(9498):1736-43.

Armstrong, D.G., et al. Debridement: The Key to Wound Healing. Podiatry Management, 2000. Dec; 6(4):627-60.

Wolcott, R.D., et al. "Biofilms and Chronic Wound Inflammation." Journal of Wound Care, 2008. Aug; 17(8):333-41.

The control group added thrombin in platelet-rich plasma at a volume of 1:10 and left for 3 minutes to form a gel. The control group used sterile forceps to gently pick up the gel and apply it to the wound.

The experimental group injected plasma and thrombin into the molding device according to the instrument operation manual, squeezed to form a gel patch, and gently picked up the gel with sterile forceps and applied it to the wound.

If there is a special need for surgery, the gel patch can be cut appropriately under sterile conditions, and the patch can be sutured and fixed with the soft tissue as needed.

The wound is sutured and covered with a dressing according to the requirements of the routine operation.

3. Specifications for the use of equipment

The sponsor shall refer to the regulations of the State Medical Products Administration on the management of medical device instructions and labels, and make appropriate labels for experimental medical devices, and mark them as "special for clinical trials of medical devices".

Records of experimental medical devices include production-related records such as production date, product model, batch number/serial number, transportation, storage, and delivery to clinical trial institutions, and post-trial recall and disposal dates.

The use of experimental medical devices is the responsibility of the clinical trial institution and the investigator, and the investigator shall ensure that all experimental medical devices are only used for subjects in the clinical trial, store and keep the experimental medical devices as required during the trial, and dispose of the experimental medical devices in accordance with relevant national regulations and agreements with the sponsor after the clinical trial. The above process needs to be handled and recorded by a special person. Investigators are not allowed to transfer the investigational medical device to any non-clinical trial participant.

4. Combined treatment (such as medication) specifications

Concomitant medications include any medications that may affect the results of this trial, such as antibiotics, analgesics, etc., which are recorded from the time the subject signs the informed consent form and continues until the subject leaves the group. Routine adjuvant medications during surgery do not need to be recorded, such as anesthetics, saline, glucose, vitamins, electrolytes and other drugs. According to the characteristics of this trial, the collected concomitant drugs were related to wound disease and other important concomitant drug treatments. Collecting information about concomitant medications should (at least) include the generic name of the drug, single dose, frequency, use, start and stop, or duration status.

(6) Bias control measures

Before the start of clinical trials, the sponsor conducts relevant training for the researchers participating in the study to ensure that the researchers fully understand the research process and are proficient in operating the test equipment.

During the clinical trial, the investigator must strictly follow the operation methods and procedures in the clinical protocol, and the clinical trial monitor should do a good job in quality control and monitoring to ensure that the researcher strictly follows the operation and implementation of the research plan. These measures are implemented throughout the implementation phase of the study to reduce errors or operational errors.

Strict stratified block randomization was used to allocate experimental groups to avoid selective bias. After the start of the trial, when the subjects meet the inclusion criteria of the trial, the investigator will confirm the subject group according to the random principle.

Subjects were screened strictly according to the inclusion and exclusion criteria of the trial protocol to reduce selective bias.

The researchers participating in this clinical trial all have relevant work experience, which ensures the proficiency and standardization of the operation.

When the clinical study is completed, do a good job of data storage and collation.

6. Statistical considerations

(1) Sample size estimation

1. Total sample size

The main evaluation indicators of this trial were that the concentration of platelets in platelet gel patches prepared by a disposable gel patch former was superior to that in platelet-rich plasma prepared under the same conditions. Therefore, this test is based on the formula:

where α=0.05, β=0.2. PC and PT are the success rates of platelet concentrations in the control group and the test group that meet the set threshold, which is the absolute value of the difference between PC and PT. ∆ is the threshold value, and the positive value is taken.

According to the clinical situation, PC is 15%, PT is 65% ，∆=0.1。 Substitution formula gives , N=36.

According to the statistical requirements, a total of 3 6 qualified cases were selected for this clinical trial to be statistically significant. According to the 5% dropout rate, 38 cases need to be selected in the end.

2. Sample size allocation and its determination basis

There are 2 clinical trial institutions in this trial, with a total sample size of 38 cases, and the actual situation can be appropriately adjusted according to statistical principles according to the expected number of disease sources, screening and inclusion power in each center, and considering factors such as center effects.

(2) Analyze the data set

1.Full Analysis Set (FAS).

A full set is as close as possible to include all randomized subjects and should generally include all enrolled subjects who have used a single device/received one treatment, and only in very limited cases can participants be excluded, including cases where important enrollment criteria have been violated and there are no observational data after enrollment.

2.Compliant with the Scheme Set (PPS).

The conformance set is a subset of the full analysis set and includes subjects who have received the treatment specified in the protocol, have observational data for the main endpoints, and have no significant violations of the trial protocol.

3.Security Analysis Set (SS).

Safety datasets should generally include all enrolled subjects who have used a device/received a treatment once and have undergone a safety evaluation.

Note: If subjects are excluded from the full analysis set and the conformance set, one must meet the definition in the protocol, and the other must fully explain the reason for exclusion, and the reason for exclusion must be clarified during the blind review.

(3) Subject exclusion criteria

In the following three situations, it is necessary to decide whether to remove them after discussion in the data review stage.

Subjects who do not meet the inclusion criteria;

Subjects who meet the exclusion criteria;

Subjects who violate/deviate from the protocol.

(4) Statistical methods

All data were statistically described, including baseline data, all efficacy indicators, and all safety indicators. Among them, the econometric data gives the mean, standard deviation, minimum, maximum and median. The counting data gives the frequency and the corresponding percentage.

The main evaluation index was the confidence interval method for the efficiency test, the pass rate of platelet concentration of the test device and the control device was counted, and the lower limit of the confidence interval between the test device and the control device CL was calculated, if [CL, ∞] Completely within the range of [ ∆, ∞], or CL > ∆, the conclusion of superiority can be concluded.

The difference test was used for the secondary evaluation indexes and safety indicators, the t-test was used for the normality and variance homogeneity of the measurement data, the non-parametric test was used for the non-normality test, and the corrected t-test was used for the normality and did not conform to the homogeneity of variance. The chi-square test or Fisher exact test was used for counting.

(5) Handling of missing values and outliers

All missing, unused, or erroneous data (including withdrawals and withdrawals) and unreasonable data will be discussed and finalized by researchers and biostatisticians during the blind data review stage. The basic statistical principles for the processing of these data are as follows:

Describe the details of each subject who drops out;

Missing data from baseline can be estimated without estimation;

Wrong and unreasonable data can be treated as missing values;

Missing values for all safety indicators are not estimated.

Monitoring plan

1.Supervision unit

Hangzhou Yuansang Biotechnology Co., Ltd

2.Monitoring time

The trial should be monitored in the early, middle, and last subjects of enrollment. In case of special circumstances, adjustments can be made accordingly.

3.Monitoring process

Understand the project status: clarify the clinical trial content, enrollment, etc.;

Appointment of visit: Make an appointment with the researcher and the teacher of the institution to make sure that the researcher and the institution have prepared all relevant materials before the monitoring.

Planned visits: Clarify the objectives of monitoring visits;

Monitoring content: check the early termination and records of subjects, check the data and signature status and signing date of the "Case Report Form", check the preservation of equipment and accessory consumables, check the quantity of equipment and accessory consumables, etc.;

Sort out the inspection results: sort out the problems found in the monitoring process and feedback them to researchers, institutional teachers, and coordinators;

Complete this inspection.

Data management

1.Data processing

Data handover

The investigator loaded the data into the electronic case report form (eCRF) in a timely, complete, correct and clear manner based on the subject's original records. The monitor monitors that the clinical trial is conducted according to the trial protocol and that all eCRFs are completed correctly and consistent with the original data. If there are any errors or omissions, the researcher should be asked to correct them in time.

Data entry and verification

Data entry:

The data entry of this trial is directly entered into the electronic data acquisition system, and the investigator or CRC will load the data into the electronic case report form (eCRF) in a timely, complete, correct and clear manner based on the subject's original observation records.

The supervisor supervises whether the test is carried out in accordance with the test plan. Verify that all eCRFs are completed correctly and consistent with the original materials. If there are any errors and omissions, ask the researcher or CRC to correct them in time. The EDC system will record all audit tracks.

The eCRF after being checked by the monitor is confirmed by the monitor and the investigator.

Data verification

Before the EDC system goes live, all computer program verification needs to pass user testing. During the enrollment process of subjects, the data will be verified in real time, and the doubts generated after the data verification will be sent directly to the research center in the EDC system, and the investigator or CRC will complete the Q&A, and the data will be verified and cleaned in real time until the final parties confirm the locked data.

All clinical trial data is recorded in the EDC as required, and the data manager checks all data in the EDC to ensure the accuracy of the data before the database is locked.

The data manager should formulate the data range check and logical check content according to the range and relationship between the values of each indicator, and write the corresponding computer program to control the wrong data input before entering, find out the cause of the error and correct it, and all the error content and modification results should be recorded and properly stored.

The electronic case report form (eCRF) is kept as required for future use after data entry and verification are completed as required. Electronic data files, including databases, inspection procedures and instruction files, should be stored in categories, and multiple backups should be stored on different disks or recording media to prevent damage.

After checking and evaluating the database data and confirming that it is correct, the database is locked. The confirmation and modification of problems found after data locking should be recorded in detail.

2.Record keeping

During the clinical trial, the investigator and sponsor are required to complete the following records:

In clinical trials, researchers should ensure that any observations and findings are recorded correctly and completely, and that case report forms are carefully completed.

Clinical trial records shall be used as original data and shall not be changed at will; If it is really necessary to make changes, the reasons shall be explained, signed and dated. Data that significantly deviates from the clinical trial protocol or is outside the clinically acceptable range should be verified, and the researcher should make necessary explanations.

The sponsor shall accurately and completely record the information related to the clinical trial, including: (1) Records of transportation and handling of the experimental medical device, including name, model, specification, batch number or serial number, name and address of the recipient, date of delivery, return of medical device samples for repair or clinical trial, date of recovery and disposal of medical device samples after clinical trials, reasons and disposal methods, etc.; (2) Agreements signed with clinical trial institutions; (3) Supervision reports and verification reports; (4) Records and reports of serious adverse events and device defects that may cause serious adverse events.

Ethics committees, clinical trial sites, and sponsors should retain clinical trial data for the following periods of time:

The ethics committee shall retain all relevant records until at least 10 years after the completion of the clinical trial.

Clinical trial institutions shall keep clinical trial data until 10 years after the end of clinical trials.

The sponsor shall preserve the clinical trial data until the medical device is not in use.

Risk-benefit analysis

1.Benefit analysis

The test device was recognized as a Class II innovative medical device in Zhejiang Province, and the product quality passed the test and met the requirements of clinical trials. The test equipment has passed the product registration inspection designated by the State Medical Products Administration, and the test result is qualified.

The clinical institutions undertaking this trial have complete instruments, equipment and technical resources.

The investigator has rich clinical trial experience, has GCP and related training, and can strictly follow the clinical trial protocol for treatment.

2. Risk analysis

36 cases met the protocol set with fewer than the statistical requirements;

failure to operate in strict accordance with the operating specifications may cause the failure of this clinical trial;

failure to strictly implement the clinical trial protocol may cause the failure of this clinical trial;

If there is an unintended change in the performance of the trial product, the clinical trial may fail.

10. Quality control of clinical trials

Each experimental institution shall conduct clinical operations in accordance with standard operating procedures and quality control procedures;

Principles such as random and parallel control can reduce selective bias and make the baseline equilibrium, so that it is comparable.

Before the start of the trial, fully train the researchers participating in the clinical trial to ensure that the researchers fully understand the trial process and are familiar with the use of the device.

During the research process, the clinical monitor strictly follows the monitoring plan to ensure that all contents of the clinical protocol are strictly complied with and the research materials are filled in in a timely and correct manner.

Clinical trial data strictly implements the data management process.

11. Ethical issues of clinical trials and informed consent

(1) Ethical considerations

This clinical trial is conducted in accordance with the Declaration of Helsinki and in strict accordance with the provisions of China's Good Practice for Clinical Trials of Medical Devices.

(2) Informed consent process

The text of the informed consent form has been prepared according to the protocol, and the specific content is shown in the sample "Informed Consent Form".

Precautions for the subject's informed consent process:

Perform the informed consent process by the investigator or delegated principal;

The informed consent process should encompass each aspect related to the target subject's decision (whether to participate in a clinical trial);

Coercion, induction, or inappropriate influence on the target subject should be avoided;

The target subject has the right to retain his or her legal rights and interests;

Easy-to-understand non-professional descriptions in the native language of the target subjects for easy understanding;

Provide sufficient time for the target subjects to read and understand the Informed Consent Form and consider whether to participate in the clinical trial;

It should contain the personal signatures of the target subject and the investigator or the investigator's designated principal;

Subjects should be provided with a signed and dated "Informed Consent Form";

It should explain how to obtain and fill in the "Informed Consent Form" in special cases such as the subject cannot handle it on their own;

Ensure that important new information is made available to new and current participants throughout the clinical trial process.

12. Regulations on adverse events and device defect reporting

(1) Definition and reporting provisions for adverse events and device defects

Adverse events are adverse medical events that occur during a clinical trial, whether or not related to the investigational medical device.

Device defects refer to unreasonable risks that may endanger human health and life safety under normal use of medical devices during clinical trials, such as labeling errors, quality problems, failures, etc.

The investigator shall record all adverse events and device defects found during the clinical trial, and jointly analyze the cause of the event with the sponsor, form a written analysis report, and put forward opinions on continuing, suspending or terminating the trial, which shall be reported to the ethics committee by the clinical trial institution's medical device clinical trial management department.

If unexpected adverse events are found in the investigational medical device, the investigator and the sponsor will jointly modify the relevant content of the informed consent form, and after reporting to the ethics committee for review and consent in accordance with the relevant working procedures, the affected subject or his/her guardian will re-sign and confirm the revised informed consent form.

Possible adverse events in this trial and how to manage them:

If the equipment is defective, replace the tested instrument in time.

If severe pain, numbness, and itching occur locally at the surgical site of the wound, the investigator should give targeted treatment to relieve symptoms according to the situation.

Localized large exudate at the surgical site of the wound, redness and swelling around the wound, increased skin temperature, and pus balls on the exudate smear should be considered as infection, and the investigator should give local and/or systemic therapy according to the situation.

The sponsor shall purchase "clinical trial liability insurance" according to relevant requirements to protect the rights and interests of subjects.

(3) Definition of serious adverse events

Serious adverse events refer to deaths or serious deterioration of health conditions that occur during clinical trials, including fatal diseases or injuries, permanent defects in body structure or body function, hospitalization or prolongation of hospitalization, and medical or surgical intervention to avoid permanent defects in body structure or body function. Causes fetal distress, fetal death, congenital anomalies, birth defects and other events.

(4) Reporting procedures and contact person information

Any serious adverse events that occur during the course of the trial and device defects that may cause serious adverse events (whether or not related to the investigational medical device) must be reported. If serious adverse events occur in clinical trials, the investigator shall immediately take appropriate treatment measures for the subject, and at the same time report in writing to the clinical trial management department of the clinical trial institution within 24 hours, and notify the sponsor and the corresponding ethics committee in writing. For serious adverse events and device defects that may lead to serious adverse events, the sponsor shall report to the filed drug regulatory department and the health and family planning department at the same level within 15 days after being notified, and shall also notify other clinical trial institutions and researchers participating in the trial, and promptly notify the ethics committee of the clinical trial institution through its medical device clinical trial management department. For deaths, the sponsor shall report to the filed drug regulatory department and the health and family planning department at the same level within 7 days after being notified, and shall notify other clinical trial institutions and researchers participating in the trial, and promptly notify the ethics committee of the clinical trial institution through its medical device clinical trial management department.

The sponsor shall accurately and completely record and report serious adverse events and device defects that may cause serious adverse events.

Research unit and contact information: Run Shaw Hospital Affiliated to Zhejiang University School of Medicine 0571-86006987

      Ningbo Sixth Hospital 0574-89007390

Sponsor and contact information: Hangzhou Yuannang Biotechnology Co., Ltd. 0571-88313603

13. Provisions on deviations from clinical trial protocols and amendments to clinical trial plans

If there are problems in the actual implementation of the clinical trial and it is necessary to revise the plan, it should be proposed to the sponsor, and after consultation and discussion by the multi-center, the responsible unit will make revisions to the plan, submit it in writing to the sponsor and all participating units for approval, and then report to the ethics committee for approval before implementation.

Non-substantive changes that do not affect the rights and interests, safety and health of subjects, or are not related to the purpose or endpoints of the clinical trial do not need to be reported in advance, but should be notified in writing to the Ethics Committee afterwards.

Deviations from clinical trial protocols that affect the rights and interests, safety, and health of the subject, or the scientific nature of clinical trials, including deviations from requests and reports. In order to protect the rights and interests, safety and health of subjects, if deviations that occur in an emergency cannot be reported in a timely manner, they shall be reported in writing as soon as possible in accordance with relevant regulations afterwards.

14. Direct access to source data and files

All source data from clinical trials are recorded in the subject's inpatient medical record, and the source data can be accessed by consulting relevant documents.

15. The content that the clinical trial report should cover

For the content covered by the clinical trial report, please refer to the "Good Management Code for Medical Device Clinical Trials" (2022 No. 1) Medical device clinical trial report template.

16. Principle of confidentiality

All information collected on subjects in the trial will be kept confidential to the extent required by law. In the study record, the subject will have an identification number. Subjects' personal information will not be released without the subject's written permission. However, the subject's records may be reviewed by the investigator, its principal agent, and the National Medical Products Administration of China or the relevant national medical device registry. The content of this trial may be published, but the personal information of the subjects will be kept confidential in any publication.

Researchers must keep the research results, plans and other information strictly confidential, and self-publishing is prohibited unless authorized in writing by the sponsor. If cited, it must also be authorized in writing by the sponsor in advance.

17. Responsibilities of all parties

(1) Responsibilities of the sponsor

The sponsor is responsible for initiating, applying, organizing, and monitoring clinical trials, and is responsible for the authenticity and reliability of clinical trials.

The sponsor is responsible for organizing the development and revision of investigator manuals, clinical trial protocols, informed consent, case report forms, relevant standard operating procedures, and other relevant documents, and is responsible for organizing the training necessary for conducting clinical trials.

The sponsor shall select the testing institution and its researchers among the qualified medical device clinical trial institutions according to the characteristics of the experimental medical device. Before signing a clinical trial agreement with the clinical trial site, the sponsor shall provide the clinical trial site and the investigator with the latest investigator's manual and other relevant documents for them to decide whether they can undertake the clinical trial.

The sponsor shall not exaggerate the mechanism and efficacy of the experimental medical device in organizing the formulation of the clinical trial plan.

During the clinical trial, when the sponsor obtains important information affecting the clinical trial, it shall promptly revise the investigator's manual and relevant documents, and submit it to the ethics committee for review and approval through the medical device clinical trial management department of the clinical trial institution.

The sponsor shall reach a written agreement with the clinical trial institution and the investigator on the relevant details of the clinical trial.

The sponsor is responsible for the safety of the investigational medical device in clinical trials. Sponsors should immediately notify all clinical trial sites and investigators and take appropriate action when it is found that it may affect the safety of the subjects or that the conduct of the trial may change the approval of the Ethics Committee to continue the trial.

If the sponsor decides to suspend or terminate the clinical trial, it shall notify the medical device clinical trial management department of all clinical trial institutions within 5 days and explain the reasons in writing. The clinical trial management department of the clinical trial institution shall promptly notify the corresponding researchers and ethics committees. Clinical trials that have been suspended shall not be resumed without the consent of the Ethics Committee.

The sponsor shall ensure that all researchers conducting clinical trials strictly follow the clinical trial plan, and if clinical trial institutions and researchers are found to be in compliance with relevant laws and regulations, this specification and clinical trial plan, they shall promptly point out and correct them; If the situation is serious or persistent, the trial shall be terminated and reported to the drug administration department of the province, autonomous region or municipality directly under the Central Government where the clinical trial institution is located and the State Medical Products Administration.

The sponsor shall bear the cost of treatment and corresponding financial compensation for subjects who suffer injuries or deaths related to clinical trials, except for damages caused by the fault of medical institutions and their medical staff during diagnosis and treatment activities.

The sponsor shall assume the responsibility for monitoring the clinical trial and select a supervisor who meets the requirements to perform the monitoring duties.

In order to ensure the quality of clinical trials, the sponsor may organize verifiers independent of clinical trials with corresponding training and experience to verify the development of clinical trials and evaluate whether the clinical trials meet the requirements of the trial protocol.

For serious adverse events and device defects that may lead to serious adverse events, the sponsor shall report to the filed drug regulatory department and the health and family planning department at the same level within 5 working days after being notified, and shall notify other clinical trial institutions and researchers participating in the trial, and promptly notify the ethics committee of the clinical trial institution through its medical device clinical trial management department.

For multicenter clinical trials, the sponsor should ensure that documents have been developed before the clinical trial to clearly coordinate the division of responsibilities between the investigator and other investigators.

For multi-center clinical trials, the sponsor shall organize the formulation of standard operating procedures in accordance with the clinical trial protocol, and organize training for all researchers participating in the trial on the use and maintenance of clinical trial protocols and experimental medical devices to ensure consistency in the implementation of the clinical trial protocol and the use of experimental medical devices.

In multicenter clinical trials, sponsors should ensure that the case report form is designed to be rigorous and reasonable to enable the coordinating investigator to obtain all data from each sub-center clinical trial site.

(2) Responsibilities of clinical trial institutions and investigators

Before accepting a clinical trial, the clinical trial institution shall evaluate the relevant resources according to the characteristics of the experimental medical device to decide whether to accept the clinical trial.

The clinical trial institution shall properly keep clinical trial records and basic documents in accordance with the agreement with the sponsor.

The investigator in charge of the clinical trial shall meet the following conditions: have relevant professional and technical titles and qualifications such as deputy chief physician, associate professor, and associate researcher in the clinical trial institution; Have the professional knowledge and experience required for experimental medical devices, and undergo relevant training when necessary; Familiar with the requirements of the sponsor and the information and literature related to the clinical trial provided by him; Ability to coordinate, control and use the personnel and equipment to conduct the trial, and ability to handle adverse events and other related events of the investigational medical device; Familiar with relevant national laws, regulations and this code.

Before clinical trials, the clinical trial management department of the clinical trial institution shall cooperate with the sponsor to submit an application to the ethics committee and submit relevant documents in accordance with regulations.

The researcher shall ensure that the relevant staff participating in the trial are familiar with the principle, scope of application, product performance, operation method, installation requirements and technical indicators of the experimental medical device, understand the preclinical research data and safety data of the experimental medical device, and master the prevention and emergency treatment methods of possible risks in the clinical trial.

The investigator shall ensure that all clinical trial participants fully understand the clinical trial protocol, relevant regulations, characteristics of the experimental medical device and responsibilities related to the clinical trial, and ensure that a sufficient number of subjects who meet the selection criteria of the clinical trial protocol enter the clinical trial, and ensure that there is sufficient time to safely conduct and complete the clinical trial in accordance with the relevant regulations within the trial period agreed in the agreement.

The investigator shall ensure that the investigational medical device is used only for the subject of the clinical trial and shall not charge any fee.

Researchers should strictly follow the clinical trial protocol and shall not deviate from the protocol or substantively change the protocol without the consent of the sponsor and the ethics committee, or without the approval of the NMPA in accordance with regulations. However, in the event of an emergency that needs to be eliminated immediately, such as when the subject is in immediate danger, it can also be reported in writing afterwards.

The investigator is responsible for recruiting the subject and talking to the subject or their guardian. The investigator is responsible for explaining the details of the investigational medical device and the clinical trial to the subject, informing the subject of the possible benefits and known foreseeable risks, and obtaining signed and dated informed consent from the subject or his/her guardian.

The investigator or other personnel participating in the trial should not force or induce the subject to participate in the trial in other improper ways.

If the investigator finds unexpected adverse events of the investigational medical device in the clinical trial, the investigator shall jointly revise the relevant content of the informed consent form with the sponsor, and after reporting to the ethics committee for review and consent in accordance with the relevant working procedures, the affected subject or his/her guardian shall re-sign and confirm the revised informed consent form.

The investigator is responsible for making medical decisions related to the clinical trial, and in the event of adverse events related to the clinical trial, the clinical trial institution and the investigator shall ensure that adequate and timely treatment and treatment are provided to the subject. When the subject has a concurrent disease requiring treatment and management, the investigator should inform the subject in time.

If serious adverse events occur in clinical trials, the investigator shall immediately take appropriate treatment measures for the subject, and at the same time report in writing to the medical device clinical trial management department of the clinical trial institution to which it belongs, and notify the sponsor in writing. The medical device clinical trial management department shall report in writing to the corresponding ethics committee, the drug regulatory department of the province, autonomous region, or municipality where the clinical trial institution is located, and the competent department of health and family planning within 24 hours. For deaths, clinical trial sites and investigators should provide all required information to the ethics committee and sponsors.

The investigator shall record all adverse events and device defects found during the clinical trial, and jointly analyze the cause of the event with the sponsor, form a written analysis report, and put forward opinions on continuing, suspending or terminating the trial, which shall be reported to the ethics committee by the clinical trial institution's medical device clinical trial management department.

Researchers should ensure that clinical trial data are included in the case report form accurately, completely, clearly, and in a timely manner. The case report form should be signed by the investigator's name, and any changes to the data should be signed and dated by the researcher, while the original record should be kept and the original record should be clearly identifiable.

Clinical trial institutions and researchers shall ensure that the data, documents, and records formed by clinical trials are true, accurate, clear, and secure.

Clinical trial sites and investigators shall be monitored, verified, and supervised by the Ethics Committee by the sponsor and provide all required records related to the trial. Where the drug administration department or the competent department of health and family planning dispatches inspectors to carry out inspections, clinical trial institutions and researchers shall cooperate.

When clinical trial institutions and researchers find that the risks outweigh the possible benefits, or have reached results sufficient to judge the safety and efficacy of the experimental medical device, and need to suspend or terminate the clinical trial, they shall notify the subjects and ensure that the subjects receive appropriate treatment and follow-up, and at the same time report in accordance with the regulations and provide detailed written explanations. If necessary, report to the drug supervision and administration department of the province, autonomous region or municipality directly under the Central Government.

Clinical trial institutions and researchers shall report to the drug administration department of the province, autonomous region, or municipality directly under the Central Government where the sponsor is located or the State Medical Products Administration if the sponsor violates relevant regulations or requests to change the trial data or conclusions.

At the end of the clinical trial, the investigator should ensure that all records and reports are completed. At the same time, researchers should also ensure that the experimental medical devices received match the quantity used, discarded or returned, and ensure that the remaining experimental medical devices are properly disposed of and documented.

Researchers can authorize corresponding personnel to recruit subjects, continuously communicate with subjects, record clinical trial data, and manage experimental medical devices according to the needs of clinical trials. Researchers should conduct relevant training for their authorized personnel and form corresponding documents.

Researchers declare

I agree:

This clinical trial was conducted in strict accordance with the requirements of the Declaration of Helsinki, current regulations in China, and the clinical trial protocol.

All required data are accurately recorded in the case report form (CRF) to complete the clinical trial report on time.

The test device is only used for this clinical trial, and the acceptance and use of the test device are completely and accurately recorded during the clinical trial process, and records are maintained.

Inspectors, verifiers, and regulatory authorities authorized or dispatched by the sponsor are allowed to monitor, verify, and inspect the clinical trial.

Strictly implement the terms of the clinical trial contract/agreement signed by all parties.

I have read the clinical trial protocol in its entirety, including the above statements, and I agree with all of the above.