Study setting {9}
The trial will be conducted at the Department of Orthopedics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, and Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, located in Shanghai, China.
Eligibility criteria {10}
Inclusion criteria
(1) X-ray examination demonstrating Kellgren-Lawrence grade II or III osteoarthritis [10].
(2) Age between 40 and 70 years, regardless of gender.
(3) Diagnosis of unilateral knee osteoarthritis, regardless of left or right knee involvement.
(4) Visual Analog Scale (VAS) score for knee osteoarthritis joint pain ≥ 3 points and ≤ 8 points (score range: 0–10 points).
(5) Willingness to provide informed consent and complete the research protocol as outlined.
Exclusion criteria
(1) Participants with previous knee surgery.
(2) Participants with acute inflammation or infection around the knee joint.
(3) Pregnant women.
(4) Participants with tumors, infections, immune system-related diseases, or poorly controlled diabetes, hypertension, and heart disease.
(5) Participants who took anticoagulants, steroids, immunosuppressants, or other drugs within 3 months before treatment.
(6) Participants with severe osteoporosis.
Who will take informed consent? {26a}
Participants diagnosed with KOA according to the criteria in the 2021"Guidelines for the Diagnosis and Treatment of Osteoarthritis [11]" by the Rheumatology Branch of the Chinese Medical Association [12]. The enrolled participants will be evaluated for eligibility by professional physicians, who will be asked to sign a written informed after voluntarily agreeing to participate.
Additional consent provisions for collection and use of participant data and biological specimens {26b}
N/A. No biological specimens will be collected in this study.
Interventions
Explanation for the choice of comparators {6b}
Both therapies were developed based on “Tuina” and “Tuina manipulation” (National TCM Higher Education "14th Five-Year Plan" Planning Textbook). Unlike regular Tuina that focus on treating the knee joint alone, the five-step knee adjustment manipulation emphasizes the overall correlation between the waist, hip, knee, and ankle. It treats the knee joint by activating and relaxing key muscles in each area and adjusting the joints.
Intervention description {11a}
Eligible KOA participants were randomly divided into treatment group and control group at a ratio of 1:1, receiving the "five-step knee adjustment manipulation" and regular knee manual therapy (Tuina), respectively. Healthy volunteers did not receive any intervention.
Treatment group
The participants in the treatment group were treated with the "five-step knee adjustment manipulation" twice a week for four consecutive weeks. The specific procedure is as follows:
(1) First Step: Posterior muscle activation
① Waist-Hip
Use the left or right palm root to perform a rhythmic spiral movement on the waist muscles on the opposite side of the affected limb. Follow this by using the elbow pressure method on the waist muscles from top to bottom, holding each point for 2 seconds. While pressing on the buttocks from center to outside on the affected side, holding each point for 1 second. Repeat the manipulation 3–5 times for each position separately, approximately 2 min.
② Lower limber
Use the left or right palm root to knead from the biceps femoris to the heel 2–3 times. Then press the biceps femoris with the elbow from top to bottom 3–5 times, holding each position for 1 second. Pressing around the popliteal fossa and rubbing the hamstrings with the thumb 2–3 times. The triceps surae is grasped and pinched from the popliteal fossa to the heel 3–5 times, approximately 1 min.
(2) Second Step: Adjust the knee and ankle joints
① Knee joint
Hold the popliteal fossa with the left hand and the middle arch with the right hand. Then right hand drives the calf into extreme external rotation through the arch, extends and everts the dorsum of the foot, left hand fixes the popliteal fossa while pressing firmly in the straight position. Repeat the manipulation 3–5 times, approximately 2 min.
② Ankle joint
Use one hand and five fingers to grasp and knead the interior and exterior sides of the ankle joint, sole of foot, and the transverse and longitudinal arch, followed by extending and everting the foot for 3–5 times, approximately 1 min.
Third Step: Anterior muscle activation
Thigh-Calf muscles
Knead and press on the quadriceps, the lateral iliotibial band, the adductor muscles, and the tibialis anterior from top to bottom with palm root and elbow separately for 3–5 times, approximately 2 min.
Fourth Step: Patellar releasing manipulation
① Patellar lifting
Grab and pinch the patella with one hand and five fingers and fix the knee joint with the other hand. Then lift the patella upward to the maximum extent for 3–5 times, approximately 1 min.
② Patellar releasing: Push the patella in four directions (up, down, right and left) with one hand palm root, and fix the knee joint with the other hand. Two hands exert force in opposite directions to stretch the patella 5–10 times, approximately 1 min. Otherwise, hold the patella with the thumb and four fingers of both hands to push the patella to move in four directions.
③ Squeezing infrapatellar fat pad
The participant lies prone with the knee semi-flexed. The therapist wraps their hands around the knee joint, with the thumbs overlapping, and places in the joint gap at the lower pole of the patella. The four fingers of both hands hold the inner and outer sides of the knee joint, respectively. While the participant slowly straightens the knee joint, the thumbs continue to press the infrapatellar fat pad vertically until the knee joint is fully straightened. Repeat the manipulation 3–5 times, approximately 1 min.
Fifth Step: Adjust the hip joint
① Relaxing the hip joint
The therapist holds the popliteal fossa of the affected limb with one hand and the lower end of the tibia with the other hand, then rotates the hip joint clockwise and counterclockwise 5 times respectively with the hip and knee flexed.
② Stretching the adductor muscles
The hip and knee of the affected limb are flexed, then abducted and externally rotated. The outer ankle is placed on the opposite thigh, crossing the legs to form a "4" shape. The therapist uses the ipsilateral hand to press down on the affected side knee and the other hand to stabilize the pelvis on the opposite. Repeat the manipulation 3 times, approximately 1 min. Do not use too much force.
③ Lower limb muscles and joints activation
The therapist stabilizes the knee joint with one hand and holds the ankle with the other hand. The participant straightens the knee joint from the hip and knee flexion position, while the hand holding the ankle provides a certain amount of resistance. Repeat the manipulation 3–5 times, approximately 1 min.
④ Stretching the posterior muscles of the lower limb
The therapist uses one hand to reach around the affected side of the popliteal fossa to stabilize the front of the knee joint, while holding the front of the sole of the foot with the other hand. Then raising the affected leg straight to the maximum and dorsiflexing the affected foot to stretch the posterior muscles for 3 times, approximately 1 min.
Control Group
The regular knee manipulation for KOA from the National Traditional Chinese Medicine Higher Education 14th Five-Year Plan textbook (Chinese Edition): "Tuina Therapy", published by China Traditional Chinese Medicine Press, is treated twice a week for four consecutive weeks. The methods are as follows:
Step 1: Relaxation manipulation:
① Relaxation knee joint: Use rolling and palm kneading around the knee joint to relax, then focus on the painful area and perform manipulations for 3–5 times, approximately 2 minutes.
② Relaxation muscles: Pinching and kneading with five fingers and palm are applied to the quadriceps femoris, with the manipulations ranging from light to heavy, depending on the participant's tolerance, approximately 3 minutes.
Step 2: Active joint manipulation
① Pressing acupoints
The selected acupoints for the Tuina treatment include EX-LE02 (Heding), EX-LE04 (Neixiyan), ST35 (Dubi), GB34 (Yanglingquan), SP9 (Yinlinquan), SP10 (Xuehai), ST34 (Liangqiu), ST32 (Futu), BL40 (Weizhong), BL57 (Chengshan), and Ashi acupoints around the knee joint (Table 1). Press the above acupoints in turn for 5 times, approximately 2 minutes.
② Joint Activation Pluck around the knee joint for 3–5 times, approximately 3 minutes.
Step 3: Adjust the knee joint
① Knee joint adduction and abduction
The participant flexes the hip and knee to 90 degrees. The therapist holds the popliteal fossa with one hand and the ankle with the other hand. Then shake the knee joint left and right for 6–7 times under the state of pulling and traction of the knee joint, approximately 3 minutes.
② Knee joint flexion and extension
To fully flex and extend the knee joint for 5 times, approximately 2 minutes. The manipulation should be gentle and slow to avoid further damage to the synovial tissue.
Step 4: Ending manipulation: Knead the affected knee with a palm, then rub around the patella and both sides of the knee joint until the participant feels warm inside the joint. Finally, both sides of the knee joint are rubbed with two palms together to relax the muscles and promote blood circulation. Approximately 2 minutes.
Criteria for discontinuing or modifying allocated interventions {11b}
Participants will be excluded if they meet the following conditions, and the reasons for withdrawing will be asked and recorded in case report forms (CRFs).
(1) Participants who cannot strictly follow the treatment course.
(2) Participants who took drugs or any other therapies prohibited by the protocol during the observation period.
Strategies to improve adherence to interventions {11c}
Participants will receive two free X-rays, 3D gaits, and one free MRI examination, while health volunteers also receive one free X-ray, 3D gait and MRI during the study. All assessments, treatments, and rehabilitation guidance for participants are provided free of charge. The research assistant will be responsible for contacting the participants for follow-up and answering any research-related questions from the participants.
Relevant concomitant care permitted or prohibited during the trial {11d}
During the trial period, no other Chinese or Western drugs for osteoarthritis and no other treatment methods are allowed, except for the regulated intervention methods. If analgesic drugs are used for KOA, outcome evaluations will be delayed until 3 days after discontinuation of medication to assess its impact.
Provisions for post‑trial care {30}
Participants could choose health education and functional exercise guidance posttrial that suited their individual needs and goals. Participants also could choose alternative treatments such as acupuncture, poultices, intra-articular glucocorticoid injections, or surgery if they were not satisfied with the efficacy of the current treatment.
Outcomes {12}
The efficacy of the intervention will be evaluated based on main and minor indicators by two independent research assistants, who are blinded to the group allocation. Endpoints will be recorded and assessed on the 2nd, 4th, 6th, 8th, 12th and 24th week after initial treatment (Fig. 2).
Figure 2 Schedule of enrollment, intervention and assessments
T1: From 7 days before enrollment to the day of enrollment
T2: 2 weeks treatment post the first treatment
T3: 4 weeks treatment post the first treatment
T4: 6 weeks post the first treatment
T5: 8 weeks post the first treatment
T6: 12 weeks post the first treatment
Baseline
The eligible participants’ general condition, including gender, group type, age, weight, and treatment history of the disease, will be recorded in CRF. The research assistants will complete the primary and secondary outcomes assessment before the first treatment.
Primary outcome
VAS
The VAS [13] scale ranges from 0 to 10 points, with 0 (starting point) representing no knee pain, and 10 (end point) representing unbearable severe knee pain. The participant will use the VAS scale to select the most severe degree of knee pain experienced in the past week.
Secondary outcomes
WOMAC
The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) [14] was developed by Bellamy and colleagues in 1988. It is a scoring system specifically designed for assessing hip and knee joint inflammation, which evaluates the structure and function of the knee joint based on pain, stiffness, and daily joint activity function.
Swelling score [15]
① No Swelling (0 point)
No visible or palpable swelling in the joints.
② Mild Swelling (1 point)
Slight swelling, lighter skin texture over the joints, and bone landmarks remain visible and palpable.
③ Moderate Swelling (2 points)
Swelling is more prominent, with minimal skin texture visible, and bone landmarks are not easily distinguishable.
④ Severe Swelling (3 points)
Significant swelling, skin appears tight and stretched, and bone landmarks are not visible or palpable.
Range Of Motion (ROM)
The ROM [16] denotes the maximum arc achievable during joint movement and is fundamental in assessing limb function. In orthopedic practice, a goniometer is commonly used to quantify ROM, typically expressed in degrees. Methodology: ① The participant assumes a prone position with the knee fully extended and relaxed. ②The stationary arm of the goniometer aligns with the greater trochanter of the femur, while the movable arm aligns with the lateral malleolus of the fibula. ③The participant actively flexes the knee joint while the observer records the degree of flexion until the end range of motion is reached.
15 meters fast-paced walk time
The 15-meter walking time [17] measurement is a valuable tool for assessing the impact of osteoarthritis on joint function and walking ability in the hip, knee, and ankle joints. This test provides a comprehensive evaluation of the effects of pain and inflammation on mobility. A stopwatch was utilized to measure the time it took the participant to walk a straight distance of 15 meters at their fastest comfortable speed.
Three-dimensional gait analysis [18]
(1) Equipment and parameters
The Smart-D 3D gait analysis system (BTS, Italy) was employed for this study. This system comprises an independent gait analysis laboratory featuring a 10-meter-long walkway situated centrally within the laboratory. The walkway is equipped with two force plates for measuring ground reaction forces. Additionally, the system includes eight high-resolution infrared cameras positioned around the walkway to capture three-dimensional motion data. Three high-definition cameras are strategically placed to provide additional visual context.
(2) Operation Method:
①Environmental Preparation
To close all doors and windows, remove all luminous objects from the laboratory and maintain a room temperature of 25℃.
②System Calibration
Prior to testing, ensure proper calibration of the system to accurately identify and calibrate the force plates, infrared cameras and video cameras.
③Participant Measurement
Measure the participant's height, weight, pelvic width, length of both lower limbs, knee width, and ankle width. Then input the measured anthropometric data into the Smart-D three-dimensional gait analysis system.
④Marker Placement
Affix body surface markers (infrared reflection fluorescent beads) at specific anatomical landmarks, including the seventh cervical spinous process, bilateral acromion, bilateral anterior superior iliac spines, median upper edge of the sacrum, bilateral greater trochanter of the femur, and bilateral heels.
Use elastic bands to secure a small stick with an infrared reflection fluorescent ball at the distal end to the middle of the bilateral thighs and the outside of the middle of the calves, ensuring parallel alignment to the ground. There are 22 marking points in total.
⑤Static Model Establishment
Instruct the participant to stand still on the force plate with raised head and chest, looking forward, and maintaining a standard standing posture for 5 seconds. Utilize the Davis KK three-dimensional model to capture various parameters of the participant during static standing and establish a static model.
⑥Dynamic Gait Analysis
After establishing the standing static model, remove the fluorescent markers from the heels and instruct the participant to walk naturally at their normal speed and habits along a 10-meter trail within the laboratory. Ensure the participant is familiarized with the environment before initiating data recording. Record gait analysis images as the participant walks, ensuring each foot step on a force plate. Collect data from three repetitions to establish a dynamic walking three-dimensional model for further analysis.
Axial alignment of the lower extremity
The axial alignment of the lower extremity [19] will be assessed on the full-length, anteroposterior and lateral radiographs of the lower limbs. Include the inferior angle of the femur, the superior angle of the tibia, the medial proximal tibial angle (MPTA) and the distal femoral lateral angle (LDFA) will be measured by an experienced orthopedic doctor.
Cross Sectional Area (CSA) [20]
The affected mid-thigh will be scanned using MRI, with a cross-sectional slice thickness set to 5 mm. After acquiring the MRI images, the cross-sectional areas of the quadriceps and biceps femoris muscles, along with fatty infiltration will be analyzed on axial T2-weighted images using the Motic Images Advanced 3.0 testing system software, which was developed by Motic Industrial Group Co., Ltd.
Biomechanical Elastic Parameters of Soft Tissues [21]
To measure the elasticity of soft tissues around the knee joint, use Shear Wave Elastography (SWE). The observation indicators include the elastic modulus values of the quadriceps femoris (rectus femoris, vastus medialis, vastus lateralis), patellar tendon, and hamstrings (semitendinosus, semimembranosus, biceps femoris).
The Aixplorer Real-time Shear Wave Elastography Ultrasound Diagnostic device (Supersonic Imaging, France) will be used, equipped with a 50 mm L4-15 linear array ultrasound probe, operating at a frequency range of 4–15 MHz. The ultrasound machine will be set to musculoskeletal mode with a measurement range of 0-300 kPa. The examination room temperature will be maintained at 25°C, and patients rested for 5 minutes before the examination.
Locations:
① Patellar tendon: From the patellar apex to the tibial tuberosity.
② Rectus femoris: At the junction of the middle and lower third of the line between the anterior superior iliac spine and the midpoint of the patellar base.
③ Vastus lateralis: At the lower third of the line between the anterior superior iliac spine and the lateral edge of the patellar base.
④ Vastus medialis: At the junction of the middle and lower third of the line between the anterior superior iliac spine and the medial edge of the patellar base.
⑤ Semimembranosus: At the junction of the middle and lower third of the line between the midpoint of the gluteal crease and the midpoint of the popliteal crease.
⑥ Semitendinosus: On the posterior medial side of the thigh, intersecting the line through the gluteal muscle and the midpoint of the popliteal crease at the junction of the middle and lower third.
⑦ Biceps femoris: On the posterior lateral side of the thigh, parallel to the semitendinosus muscle.
Operation Methods:
① The participant assumes a prone position with the hip joint in neutral rotation and the knee joint fixed at 30 degrees of flexion using a brace. Meanwhile, measurements of the knee extensor group and patellar tendon are taken.
② An experienced sonographer with over 10 years of ultrasonography experience performed both gray-scale and elastic ultrasound on the patellar tendon and knee extensors. To ensure good contact between the probe and the skin, an adequate amount of gel will be used. Initially, a conventional two-dimensional ultrasound examination was conducted with a uniform depth setting of 3–4 cm. The patellar tendon and extensors will be scanned longitudinally along the tendon and muscle. Then, the elastography mode will be activated, and the rectangular region of interest will be set to the system’s maximum size of 13.5 × 12.5 mm. When measuring the elastic modulus using the Q-box quantitative analysis system, the Q-box diameter will be adjusted according to the thickness of the tendon or muscle. The system automatically calculated the average, maximum, and minimum elastic modulus values (kPa) of the tendon and muscle within the Q-box region. The average elastic modulus will be selected for statistical analysis. For hamstring measurements, the participant remained in the prone position with the knee joint naturally extended. The ultrasound examination will be performed similarly to the prior measurements.
Participant timeline {13}
The schedule of enrollment, interventions, assessments, and participant visits are shown in Fig. 2. The research assistant will arrange the next treatment or follow-up appointment with the participant and notify them 1–2 days in advance via phone or WeChat.
Sample size {14}
This study was designed with the Visual Analog Scale (VAS) score as the primary outcome indicator to assess pain levels. The control group received regular manipulation therapy for KOA. Based on our previous small sample case observation, we anticipate this difference to be maintained at the 12-week follow-up, with the VAS score of the control group improving by 1.78 points, while the treatment group will improve by 3.39 points. The following statistical parameters were used for the study design: unilateral α (type I error rate) = 0.25, β (type II error rate) = 0.1, standard deviation (σ) = 1.32, Δ = 1/2 of the standard deviation. The ratio of the number of cases in the experimental group to the control group (K) = 1.
The following formula was used to calculate the required sample size for each group:
nc =\(\:\frac{\:{({\text{Z}}_{1-{\alpha\:}}+{\text{Z}}_{1-{\beta\:}})}^{2}{{\sigma\:}}^{2}(1+\frac{1}{K})}{{({\mu\:}\text{r}-{\mu\:}\text{c}-△)}^{2}}\)
nr= Knc
The initial sample size was n = 35 per group. Considering a 20% shedding rate, and three research centers, with central factors, the sample size was increased to 60 cases in the control group and 60 cases in the treatment group. Then 40 participants per center (20 in the treatment group and 20 in the control group). Additionally, 45 healthy volunteers were included in the study. Each center is responsible for 15 healthy volunteer cases.
Recruitment {15}
Recruitment posters for the study will be posted in prominent locations in the Shanghai Municipal Hospital of TCM outpatient clinic. In addition, the recruitment advertisements will be posted on Shanghai Municipal Hospital of TCM's official WeChat public account to reach a wider audience and increase visibility.
Assignment of interventions: allocation
Sequence generation {16a}
Eligible participants will be randomly allocated in a 1:1 ratio to either the Five-step group or the Regular group. The randomization method was undertaken by the Statistics Group of the Clinical Evaluation Center of Shanghai Municipal Hospital of TCM. The randomization was concealed using a central control scheme. After each center enrolled participants, it obtained a random number from the Clinical Evaluation Center and then carried out treatment interventions based on the random number.
Concealment mechanism {16b}.
The randomization program and list, comprising the code, randomization number, and treatment regimen for each participant, will be concealed in an opaque envelope. The administration of the randomization process will be overseen by the Clinical Evaluation Center.
Implementation {16c}
The Clinical Evaluation Center will inform the manipulation therapies about the participant’s randomization number and treatment group by text or WeChat.
Assignment of interventions: Blinding
Who will be blinded {17a}
While the manipulation therapies will not be blinded to interventions due to they have to know which intervention they use for participants, the participants, outcome evaluators and biostatisticians will be blinded to group details.
Procedure for unblinding if needed {17b}
The following situations will be unblinded and the specific reasons will be recorded in the CRF:
(1) When the study and data analysis are completed.
(2) Participants actively or passively withdraw from the study. (As shown in 11b.)
Data collection and management
Plans for assessment and collection of outcomes {18a}
Specialized research assistants, who are blind to the allocation, will assess the primary and secondary outcomes at the timepoints during the study (Fig. 2). Research assistants at each center will receive standardized training in outcome measurement and assessment before the start of the study.
Plans to promote participant retention and complete follow-up {18b}
We will provide professional rehabilitation guidance for participants during the later stages of the study. Additionally, the dedicated individual will be responsible for answering participants' daily questions. Finally, the transportation subsidy of participants who complete the follow-up will be paid.
Data management {19}
The data collection work is the responsibility of two independent research assistants. The data entry adopts the double input method, and all patient-related data will be stored confidentially. Once data extraction and statistical analysis are completed, the CRFs will be securely locked in the research office cabinet and managed by the research organizer. All assistants will receive a training course before conducting the study.
Confidentiality {27}
We will strictly protect all participants’ private information in accordance with the law and will not use participants’ identities, phone numbers, or contact addresses for any commercial purposes. Anyone who wishes to access the patients' original medical records must obtain permission from the research sponsor and regulatory authorities.
Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use {33}
N/A. No biological specimens will be collected in this study.
Statistical methods
All analyses will follow the intention-to-treat principle, analyzing each participant according to their randomized treatment assignment. Non-compliance with treatment requirements and withdrawals will be ignored in the preliminary analysis. Missing data will not be included in the initial analysis. If data are assumed to be missing at random, the multiple imputation method will be used to handle the missing data. Epidata V3.1 will be used for data input. All statistical tests were two-sided, and P < 0.05 indicated that the difference tested was statistically significant. The specific statistical analysis included three parts: (1) baseline data analysis; (2) efficacy analysis; (3) safety analysis. Data conforming to a normal distribution will be expressed as mean ± standard deviation (x ± s). The treatment effect data within the same group over time will be analyzed using one-way ANOVA for continuous measurements. If statistical significance is found, the Least Significant Difference (LSD) test will be used for pairwise comparisons. Differences in treatment effects between groups will be analyzed using one-way ANOVA. If statistical significance is found, the LSD test will be used for between-group comparisons. All analyses will be performed using SPSS 26.0, with a test level of α = 0.05 and P < 0.05 as statistically significant.
Interim analyses {21b}
N/A. Previous research findings, coupled with our clinical treatment observations, suggest that manipulation can effectively relieve the symptoms of KOA. Additionally, due to the minimal incidence of advent effects and complications associated with manipulation, the interim analysis was deemed unnecessary.
Methods for additional analyses (e.g. subgroup analyses) {20b}
N/A. The primary aim of this study is to evaluate the difference in the efficacy of two manipulation techniques for KOA.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
We will use imputation to handle missing values:
(1) If the missing attribute value is numeric, it will be filled in using the average value of that attribute from all other objects.
(2) If the missing attribute value is non-numeric, it will be filled in using the most frequent value of that attribute from all other objects, following the majority principle in statistics.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
The protocol for this study is publicly available at the China Registered Clinical Trial Registration Center (ChiCTR2400085536). CRF data will be shared on the clinical trial public management platform ResMan (www.medresman.org.cn) after the trial ends.
Oversight and monitoring
Composition of the coordinating center and trial steering committee {5d}
The trial steering committee, comprising the senior supervisor, the Clinical Research Center director, and the ethics committee, who will offer essential monitoring and daily support throughout the trial.
Composition of the data monitoring committee, its role and reporting structure {21a}
The entire process of this trial will be supervised by three-level monitors. The first-level monitor, composed of researchers with manipulation technology certification, will be responsible for the entire progress of the study. The second-level monitor, composed of researchers from the ethics committee, will be responsible for supervising the study. The third-level monitor, composed of data supervisors, will ensure the authenticity of the data. Given that no problems harmful to the participants are expected, no interim analysis will be conducted.
Adverse event reporting and harms {22}
(1) Adverse event (AE) recording and reporting methods
AE that occurs during the study may not necessarily have a causal relationship with treatment, but the severity of symptoms, time of occurrence, duration, and treatment measures should be recorded in the CRF, and their relevance to the experimental treatment method should be evaluated and followed up. The classification of adverse events is recorded according to the CTCAE43.0 five-level scoring system.
(2) Treatment of serious adverse events (SAE)
SAE refers to events that cause death, permanent or significant disability, permanent damage to organ function, or result in hospitalization or prolonged hospitalization. The researcher should immediately take necessary measures to ensure the safety of the subject in the event of an SAE, and must report the SAE to the sponsor and the ethics committee within 24 hours. If the SAE requires emergency unblinding, the clinical trial center and the blind editor should jointly perform the unblinding. The researcher will then decide on further treatment measures based on the unblinded information.
Frequency and plans for auditing trial conduct {23}
Both the ethics committee and data supervisor will review the progress of the study and the authenticity of the data biannually.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Any modification of the protocol must be approved by the study organizer, the ethics committee, and the clinical research center. Additionally, all modifications must be updated in the clinical research registration center.
Dissemination plans {31a}
Upon completion of the research, the results will be published as articles in both domestic and international journals.