Study design
The study will be conducted from May 2024 to March 2026 at Guangdong Provincial Hospital of Chinese Medicine and will be performed according to the Declaration of Helsinki.
This is a randomized controlled, parallel, single-center prospective clinical trial. The study has been approved by the Ethics Committee of Guangdong Provincial Hospital of Chinese Medicine and was registered on the clinical trial platform (ClinicalTrails.gov ID: NCT06328153; Protocol ID: BF2022-101).
Study setting
Participants are recruited from the outpatient department of Guangdong Provincial Hospital of Chinese Medicine. Eligible and consented participants are randomly assigned at a ratio of 1:1 to receive treatment in the FSN group (n = 30) or drug group (n = 30) for 2 weeks. Participants are assessed at baseline and on the 7th, 14th, 28th, and 42nd days after the start of the intervention. The design of the trial is summarized in Fig. 1.
Participants
Inclusion criteria
Participants who meet the diagnostic criteria for KOA according to the Guidelines for the Diagnosis and Treatment of Osteoarthritis (2018 Edition) by Osteoporosis Group of the Chinese Orthopaedic Associationg21 and the diagnostic criteria for KOA formulated by the American College of Rheumatology22 are eligible to participate when they also meet the following criteria:
The patients are aged between 60 and 80 years.
BMI < 28.
Kellgren-Lawrence grade 1–3.
Knee pain score > 3 on a 10-point numerical rating scale (VAS).
Voluntary and capable of signing the informed consent form.
Exclusion criteria
Nonprimary knee osteoarthritis, such as gouty arthritis, hemophilic arthritis, or knee osteoarthritis, is caused by serious violence withsevere damage to the structure of the knee joint damaged.
According to the above guidelines, the affected knee severely deformed, either clinically or radiologically.
Patients who have taken analgesics or Nonsteroidal Antinonsteroidal anti-inflammatory Drugsdrugs (NSAIDs) orally or topically on the affected knee within the last month; who have received adjuvant treatment for the affected knee joint (e.g., physical therapy, acupuncture, massage, etc.) within the last 3 months; or who have a history of knee surgery in the past 6 months.
With other diseases that may cause lower limb pain, such as lumbar disc herniation and lumbar spinal stenosis.
With lower extremity vascular diseases.
With Severe systemic or lower limb local skin diseases.
With any unstable medical disease (e.g., acute cardiac or cerebrovascular disease, poorly controlled diabetes, etc.) or psychiatric illness.
With contraindications to NSAIDs, which include postcoronary artery bypass graft surgery, active peptic ulcer, severe heart failure, etc.
Sample Size Calculation
The main outcome measure of this study is the decrease in VAS score from baseline during the 2-week treatment period. FSN, an emerging acupuncture method, has been studied in randomized controlled trials19 20.. However, both of these previous studies used superiority testing, which cannot provide an appropriate reference for the sample size calculation of our study. Therefore, we refer to a randomized controlled trial that compared electroacupuncture with an NSAID for treating KOA23. We assume that the effect sizes of interventions (FSN and celecoxib) in this trial were similar to those (acupuncture and diclofenac applied for interventions) in the aforementioned study. The results of the above study showed that the VAS score decreased by 48.24 ± 3.59 mm from baseline after 4 weeks of electroacupuncture treatment, and by 32.99 ± 3.94 mm from baseline after 4 weeks of oral administration of diclofenac. The actual difference in the VAS score between the two interventions after 4 weeks of treatment was 15.25 mm, with a combined standard deviation of 3.85 mm. However, since the course of treatment in our trail is half of that in the aforementioned study, appropriate adjustments for the expected difference in the VAS score are needed. Based on our clinical experience, the efficacy and the treatment period cannot be considered to increase in full equivalence, and since the 2-weeks intervention course is relatively short, we would not expect the cumulative efficacy to be half that of the 4-weeks intervention in the aforementioned study.
Therefore, to compare the efficacy of FSN and celecoxib, we assume that the difference in two groups’ means of the changes in the VAS score is 6.5mm after 2 weeks of treatment, which is slightly less than half the difference observed in the reference trial23 after 4 weeks of intervention. Assuming a 1:1 ratio of participants in the 2 groups, the NIM (Non-Inferiority Margin) is defined as 10 mm. A two-sided test with a significance level (α) of 0.05 and a power(1-β) of 0.80 is applied. With a possible dropout rate of 10%, using the PASS 15.0 software, 60 participants shall be included in this study.
Randomization and blinding
Eligible and consenting participants are randomly assigned to the FSN group (n = 30) or the drug group (n = 30) for the clinical study at a 1:1 ratio through a central randomization system. The randomization sequences are generated by staff using the SAS program. Patient serial numbers, random numbers, and grouping results are assembled into random assignment cards that are then sealed in disposable opaque envelopes. The cards in the envelopes have serial numbers that match the numbers on the envelopes. The random assignment cards are kept in a special place. When eligible participants enter the study, envelopes with the same serial numbers are opened in the order of the participants. Participants are grouped and treated according to the cards they obtain.
Due to the specific nature of the needling operation, the participants and practitioners involved in this study are not blinded. However, the researchers who are responsible for data collection and statistical analyses are blinded to the assigned tasks to minimize bias in the reporting of subjective results.
Interventions
Participants’ gender, age, marital and childbearing history, family history, allergy history, smoking and drinking history, past medical history, drug history, and other general information are collected before the formal intervention. The participants' baseline data, such as weight and BMI, are observed. Visual analogue scale (VAS) measurements, Western Ontario and McMaster Universities (WOMAC) index measurements, joint active range of motion tests, three-dimensional gait analyses, and shear wave elastic imaging technology analyses are performed to comprehensively evaluate the pain level, knee joint movement status and system function, as well as the lower limb skeletal muscle elastic modulus.
FSN Therapy
Operation of the FSN follows the KOA’s Fu’s Subcutaneous Needling Treatment Code of Practice24. Participants first assume the supine position. After routine disinfection, a disposable Fu’s subcutaneous needle (Nanjing Paifu Medical Technology Co., Ltd., Jiangsu, China) is inserted parallel into the subcutaneous loose connective tissue around the pathological tight muscles (gastrocnemius muscle, tibial anterior muscle, and quadriceps femoris muscle). The protruding part of the hose holder is fixed to the card slot after the needle is completely inserted. Confirming that the participants have no pain, the index and ring fingers alternate back and forth in a smooth, soft, fan-like swaying movement. The fan angle is approximately 60°, and a total of 45 round trips are performed in 30 seconds. Swaying Movement is accompanied by Reperfusion Approach: 20 sways along with 10 seconds of Reperfusion Approach are performed as a set of procedures. For each target pathological tight muscle, 2–3 sets of the above procedures are required. The Reperfusion Approach for different pathological tight muscles are as follows: (1) for the gastrocnemius muscle, the participant is placed in the prone position, with the foot extended out of the bed. A towel is placed on the soles of the feet, and the participant is instructed to resist resistance by plantar flexion of the ankle joint; (2) for the tibialis anterior muscle,the participant is placed in the supine position, and the ankle is dorsiflexed to resist counterdirectional forces from the instructor, (3) for the quadriceps muscle,the participant is placed in the supine position. With a foam shaft or other support made of soft material placed in the popliteal fossa, the knee joint is then forcefully extended against resistance from the instructor. The FSN group is treated 3 times a week for 2 weeks. (Fig. 2)
Oral Celecoxib
Participants in the drug group receive 200 mg of oral celecoxib (a capsule) every day continuously for 2 weeks. They are closely followed up during the administration of the drug, and the treatment will be discontinued immediately in case of adverse events. If necessary, appropriate symptomatic treatments, such as acid suppressing, protection of the gastric mucosa, antidizziness, etc., will be administered until the adverse events subside.
Outcomes
The evaluators detect the outcomes at baseline, day 7, day 14, and during the follow-up period (day 28 and day 42 after the start of the treatment) (Table 1).
Table 1
Period
|
Admission day
|
Baseline assessment
|
Evaluation on Day 7
|
Evaluation on Day 14
|
Follow-up period
|
Time point
|
-T1
|
T0
|
T1
|
T2
|
T3
|
Enrolment
|
|
|
|
|
|
Eligibility
|
⭕
|
|
|
|
|
Informed consent
|
⭕
|
|
|
|
|
Allocation
|
⭕
|
|
|
|
|
Interventions
|
|
|
|
|
|
FSN
|
|
|
⭕
|
⭕
|
|
Celecoxib
|
|
|
⭕
|
⭕
|
|
Evaluation
|
|
|
|
|
|
VAS score
|
|
⭕
|
⭕
|
⭕
|
⭕
|
WOMAC score
|
|
⭕
|
⭕
|
⭕
|
⭕
|
ROM
|
|
⭕
|
⭕
|
⭕
|
|
3D gait analysis
|
|
⭕
|
⭕
|
⭕
|
|
Shear wave elastic imaging
technology analysis
|
|
⭕
|
⭕
|
⭕
|
|
Adverse events
|
|
|
⭕
|
⭕
|
⭕
|
Primary outcome
We assess and compare improvements in knee pain symptoms within and between the two groups using the difference between the VAS score (0-100 mm) on day 14 and the baseline value as the primary outcome.
Secondary outcome
VAS
We assess patients' knee pain using the VAS on day 7 and during the follow-up period as secondary outcome indicators.
WOMAC
We adopt the Western Ontario and McMaster Universities Arthritis Index (WOMAC) as a pretrail assessment. As the trail progresses, we assess the WOMAC score on day 7 and day 14, and during the follow-up period to evaluate and compare the improvements in knee mobility as well as ability to perform activities of daily living within and between the two groups.
Range of Motion (ROM)
The ROM is assessed at baseline, on day 7 and day 14, and during the follow-up period to reflect the functional status of the knee joint.
Three-dimensional Gait Analysis
An Opti-Knee 3D motion analysis system equipped with Guangdong Provincial Hospital of Chinese Medicine is used. Participants are asked to undergo approximately 2–3 minutes of acclimatization, and after their bony markings on the body surface are well marked for positioning, the participants walk continuously on the exercise board in a natural habitual position at a constant speed of 3.0 km/h. Subsequently, the system collects gait data at a frequency of 60 frames/s and an acquisition time of 15 s, including six degrees of freedom (femoral relative to tibial internal/external rotation angle, internal/external flip angle, flexion/extension angle, anterior/posterior displacement, superior/inferior displacement, and internal/external displacement). The above data are then exported in the form of single-cycle gait data (Fig. 3).
Shear Wave Elastic Imaging Technology Analysis
A Supersonic Aixplorer Color Doppler Ultrasound Diagnostic Unit equipped with Guangdong Provincial Hospital of Chinese Medicine is used. Participants are assure that the whole body muscles are in a relaxed state, and that the legs are naturally straight and unfolded. First, 2D ultrasound is used to identify the muscles. The device is then switched to the SWE mode, with an L15-4 line array probe and a frequency of 4 ~ 12 MHz. The ultrasound is set to muscle examination mode during the examination. The probe is lightly placed at the midpoint of the examined muscle belly, and it is parallel to the direction of the muscle fibers. With no pressure applied, in terms of depth, skeletal muscles can be regarded as having three layers: the upper layer, the middle layer, and the lower layer. In the ultrasound display, the middle layer is taken to place the sampling box for quantitative analysis. After 5 seconds, the image is frozen as the shear wave pattern in the box is stable and uniform. The Q-BOX function is launched, with the measurement area set as a 5-mm circle, and the system automatically calculate the mean value of Young's modulus for the muscle tissues in the Q-BOX (Mean). Each frozen image is repeated 3 times, and the mean values of 2 qualified sampling boxes are taken for statistical analysis (Fig. 3).
Assessment of safety
Unfavourable or unintended events among participants, such as subcutaneous haemorrhage or haematoma caused by FSN (reported by participants during or after the treatment and assessed immediately by the acupuncturist), as well as gastrointestinal reactions caused by the administration of celecoxib (recorded during medication or at the follow-up visit), are documented using a preset questionnaire. Appropriate measures are then taken. If a more serious adverse reaction develops and the investigator considers the participant unfit to proceed with the study, the experimental interventions for this participant will be promptly terminated.
Statistical analysis
All the statistical tests are conducted using a bilateral test, with P < 0.05 indicating a statistically significant difference. The Mean ± standard deviation is used for normally distributed measurement data. Nonnormally distributed data are presented as the median and interquartile range. Differences in data on outcome measures from baseline to each evaluation time point are analyzed using independent sample t tests or Mann-Whitney U tests, as appropriate, between groups; paired t tests or Wilcoxon tests are used to compare differences in the data for each outcome index at each evaluation time point within the group. In addition, the VAS and WOMAC evaluations are repeated 5 times in this study. Therefore, repeated measures analysis of variance are used for auxiliary analysis. Baseline data (including age, sex, BMI, etc.) are controlled for as confounding factors. Multiple imputation methods are adopted for the analyses of missing data. A generalized linear mixed model is further used for analyses of nonnormally distributed and partially missing data, as the interaction effects are also analyzed. SPSS 25 software (IBM SPSS Statistics, New York, USA) is used for the data analyses. Data analyses are conducted by a data analyst who is unaware of allocation and treatment.
Ethics
The research results of this project may be published in medical journals, but we will keep the patient's information confidential by legal requirements. Unless required by relevant laws, the patient's personal information will not be disclosed. When necessary, government management departments, hospital ethics committees, and their relevant personnel can access patient information according to regulations.
Researchers or researchers who are authorized personnel are responsible for explaining the benefits and risks of participating in the trial to each patient, their legal representative, or a notary witness and should obtain written informed consent before the patient enters the trial. The original informed consent form signed and dated by all participants or their legal representatives, as well as the person presiding over the informed consent process, will be kept by the researchers.
Dissemination and data sharing
The study will be reported according to the Consolidated Standards of Reporting Trials (CONSORT) statements. The results of their data will be disseminated to participants through interviews held with nurses. The final manuscript will be completed by the first two authors and the authorship of the final manuscript will depend on the actual contribution. The study results will be distributed using a broad dissemination strategy, including oral presentations at international meetings and publications in peer-reviewed international journals.