Study setting {9}
The trial will be conducted at the Department of Orthopedics Clinic, Shanghai Municipal Hospital of Traditional Chinese Medicine, located in Shanghai, China.
Eligibility criteria {10}
Inclusion criteria
(1) Participants diagnosed with KOA according to the Chinese guideline for the diagnosis and treatment of osteoarthritis (2021 edition) [12]
(2) Aged 45–75 years (either sex)
(3) Unilateral or bilateral chronic knee pain for the last 1–6 months
(4) Radiologic confirmation of KOA (Kellgren–Lawrence grade II or III [13]
(5) VAS score ≥ 40 mm in the last week
(6) Written informed consent
Exclusion criteria
(1) History of knee arthroplasty or preparing for any knee surgery for either knee, arthroscopy in the last 12 months or an intra-articular injection within the past 6 months
(2) Knee pain caused by other diseases (such as trauma, fracture, infection, autoimmune diseases, malignant tumours, severe arthrohydrops, etc.)
(3) Received acupuncture treatment in the last 3 months, needle phobia
(4) Serious acute or chronic organic diseases or psychiatric disorders
(5) Pregnant or breastfeeding
(6) Blood coagulation disorders
(7) Cardiac pacemaker
(8) Participated in other clinical trials in the past 3 months
Who will take informed consent? {26a}
Eligible participants are fully informed about the purpose, procedure, potential risks, and benefits in this trial. Eligible participants will be asked to sign a written informed consent form after fully understanding all aspects of the trial and 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 groups’ acupuncture prescriptions were developed based on Chinese Medicine Meridian Theory and expert consensus [14], and Zha Tiao group incorporating the theory of Tiaodong acupoint [9]. The main difference between the two groups of electroacupuncture therapy is the use of the De Qi manipulation technique. And the Zha Tiao EA group emphasized combining the objective phenomenon of De Qi with the subjective feelings of the patients, while De Qi in the regular EA group depend on the subjective feelings of doctor and participants.
Intervention description {11a}
For participants with bilateral knee OA, both knees will be needled, while only the affected knee will be treated for those with unilateral OA symptoms. All acupuncture treatments will consist of 30-minute sessions administered three times a week for a total of 4 weeks, ideally with sessions scheduled every other day. Disposable sterile needles (length: 25–40 mm, diameter: 0.25 mm; Hwato, Suzhou, China) and BT701-1B Electro-Acupuncture (EA) devices (Shanghai Huayi Co., Ltd, Shanghai, China) will be utilized for acupuncture. The prescription includes four obligatory acupoints and two adjunct acupoints, which are utilized in both the ZT-EA and R-EA groups. The obligatory acupoints consist of Xuehai (SP10), Diji (SP8), Liangqiu (ST34), Zusanli (ST36), while the adjunct acupoints are Neixiyan (EX-LE5) and Dubi (ST35) (Fig. 2, Table 1).
ZT-EA Group
Zha Tiao acupuncture manipulation will be performed on each obligatory acupoint until achieving De Qi, characterized by patient’s local muscle twitching and subjective sensations such as muscle twitching, soreness, numbness, distention, and heaviness. The regular manipulations, such as lifting, thrusting, twisting, and rotating, will be used for adjunct acupoints to achieve De Qi.
The manipulation of Zha Tiao acupuncture is divided into four steps:
(1) Location: Using the left thumb or index finger to palpate the acupoint, applying gentle pressure to assess the thickness of the muscle and the width of any cleft or depression. Additionally, carefully sensing the tendons and vessels beneath the acupoint to determine the appropriate angle and depth for needle insertion, ensuring to avoid damaging them.
(2) Fixation: After locating the acupoint, stabilize it with the left hand to prevent sliding and to separate any tendons or vessels. Ensure the acupoint is held in a relatively stable position. Then, prepare to feel the twitching of the triggering muscle fibers under the needle. Prioritize gentle handling to ensure patient comfort and safety during the procedure.
(3) Exploration: With the cooperation of the left hand, insert the needle to the level of the muscle using the right hand. Then, perform an orderly fan-shaped search along the vertical plane of the meridians where the acupuncture points are located using a small and gentle lifting and inserting technique. This search doesn’t cease until local muscle twitches are elicited and the patient feels a strong sensation. It's crucial to avoid irregular lifting, inserting, and twisting around the point to maintain precision and ensure the effectiveness of the technique.
(4) Activation: After eliciting muscle twitching, the needle will be maintained at a specific angle, direction, and depth. Simultaneously, the acupuncturist will continue to stabilize the acupoint with the left hand, gently lift and insert the needle with the right hand. This technique aims to repeatedly activate muscle twitching and needle sensation, promoting the reduction of muscle tension.
R-EA Group
The R-EA group will undergo regular manipulation techniques, including lifting, thrusting, twisting, and rotating, until achieving De Qi. De Qi is characterized by sensations such as soreness, numbness, distention, and heaviness.
All disposable acupuncture needles will be vertically inserted to a depth of 25–30 mm after sterilization of the target acupoints [15]. For both groups, paired electrodes from the EA apparatus will be attached to the needle handles at Xuehai (SP10) and Zusanli (ST36), Liangqiu (ST34) and Diji (SP8) by the research assistants (Fig. 2, Table 1). The wave will be set at 2/100 Hz with an intensity ranging between 3–4 mA. The electric current will be gradually increased until the needles begin to vibrate noticeably, while ensuring closely monitoring to maintain patients’ safety throughout the procedure.
Criteria for discontinuing or modifying allocated interventions {11b}
Participants who meet any of the following criteria will be withdrawn from this study. And the research assistant will ask the patient’s reasons for withdrawing and record data in detail using case report forms (CRFs).
(1) The condition of patient's knee worsens and the pain cannot be alleviated by acupuncture (based on a VAS score ≥ 8 points).
(2) Any serious adverse events occur, such as severe infection, coma, shock or death.
(3) Participants can withdraw from the study at any time for any personal reasons.
Strategies to improve adherence to interventions {11c}
All assessments, treatments, and rehabilitation guidance during the trial protocol will be provided free of charge. Additionally, participants will receive one free X-ray and MRI examination before the end of the study. After each intervention, appointments for the next visit will be scheduled with research assistants, who will also provide reminders via phone or WeChat one day in advance. To assist participants in managing their appointments and follow-ups, personalized treatment cards will be provided. These cards will include specific dates and times for the next follow-up appointment, serving as a convenient tool for participants to ensure timely attendance.
Relevant concomitant care permitted or prohibited during the trial {11d}
Participants will be provided with celecoxib capsules (Sichuan Guowei Pharmaceutical Co., Ltd., 200mg*20#, 1 capsule per day) in the event of intolerable pain (VAS ≥ 8) during the research. Detailed records of the medication, dosage, and duration of use will be maintained. Additionally, outcome evaluations will be delayed until 3 days after discontinuation of medication to assess its impact.
Provisions for post-trial care {30}
At the end of the study, patients will have the option to choose between two main treatment pathways. They can opt for free acupuncture treatment for four weeks, with sessions scheduled based on their preferences and availability. Alternatively, patients may choose to receive health education and functional exercise instruction tailored to their individual needs and goals. In addition to these options, alternative treatments such as massage, plasters, intra-articular glucocorticoid injections, or surgery will be available if patients feel dissatisfied with the curative effect of their chosen treatment pathway.
Outcomes {12}
Primary outcome
VAS And WOMAC
The Visual Analogue Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score will be measured from baseline to 12 weeks.
The VAS [16] is a pain intensity scale used in questionnaires, where participants indicate their pain level by marking a point on a line ranging from 0 mm (denoting no pain) to 100 mm (indicating intense pain). During evaluation, participants will be asked to select the location on the line that best represents their severe pain score over the past week. The WOMAC Osteoarthritis Index [17] is a multidimensional self-assessment questionnaire designed to comprehensively evaluate symptoms associated with osteoarthritis of the lower limb, encompassing pain (5 items), stiffness (2 items), and physical function (17 items). Symptom severity is categorized into five levels (none, mild, moderate, severe, and very severe), with scores of 0, 1, 2, 3, and 4, respectively. The total score of the scale is 96 points, reflecting the cumulative symptom burden experienced by the individual. The WOMAC Index serves as a valuable tool for assessing the impact of osteoarthritis on daily activities and monitoring treatment efficacy.
Secondary outcomes
Range Of Motion (ROM)
Range of Motion (ROM) refers to the extent or limit to which a part of the body can be moved around a joint or a fixed point [18]. In this research, active knee joint flexion and extension ROM will be used as observation indicators. ROM will be measured in degrees using a goniometer, with its axis aligned with the lateral gap of the knee joint. The fixed arm of the goniometer will align with the long axis of the femur, while the moving arm will align with the long axis of the calf. The maximum angle of natural extension of the knee joint will be measured with the patient in a supine position, and active flexion of the knee joint will be measured with the patient in a prone position. The end degree of joint flexion angle will be recorded. Additionally, the rotation angle will be tested at 90° flexion of the knee joint. Each angle measurement will be performed three times, and an average value will be calculated.
15 meters fast-paced walk time
The 15-meter fast-paced walk time measurement is utilized to evaluate the impact of pain and inflammation on joint function and walking ability in individuals with osteoarthritis affecting the hip, knee, and ankle joints [19]. Before and after treatment at each time point, participants will undergo the 15-meter fast-paced walk test, during which they will walk as quickly as possible along a designated pathway. The time taken to complete the 15-meter distance will be measured using a stopwatch.
Axial alignment of the lower extremity
The axial alignment of the lower extremity plays a crucial role in evaluating the severity and prognosis of knee joint degeneration in patients [20]. To assess axial alignment, anatomical landmarks such as the centers of the femoral head, knee, and ankle will be identified by a senior doctor. Subsequently, angles between the mechanical axis of the lower limb and the mechanical axes of the femur and tibia will be measured. Additionally, the medial proximal tibial angle (MPTA) and distal femoral lateral angle (LDFA) will be measured to further evaluate lower extremity alignment [21].
Lower limb strength [22]
The patient will be seated with their knee flexed at a 90° angle, ensuring a standardized position for muscle strength assessment. One end of the simplified tensile force gauge will be fixed, while the other end will be tied to the patient's ankle on the affected limb. Subsequently, muscle strength of the quadriceps and biceps femoris will be measured and recorded while performing maximal flexion and extension of the knee joint. The patient will be instructed to perform these movements to their full range of motion, allowing for an accurate assessment of muscle strength.
Cross Sectional Area (CSA) [23]
The affected knee will undergo Magnetic Resonance Imaging (MRI) scan at a 3.0T system (GE SIGNA™ Premier), with a slice thickness and interslice gap of 3.5mm. The CSA of the quadriceps and biceps femoris muscles, along with fatty infiltration, will be measured on axial T2-weighted images using Image processing software (Image J) at six consecutive levels of the patellar upper pole. Subsequently, the percentage of fatty infiltration (FI) will be calculated using the formula: fatty CSA / (functional muscle CSA + fatty CSA) ×100%.
12-Item Short Form Survey (SF-12)
The SF-12 [24] questionnaire will be utilized to assess the quality of life of each participant. This questionnaire encompasses 8 domains and provides scoring for both physical and psychological components. Physical dimension: total scores range from 0 to 100; lower scores indicate a worse quality of life. Mental dimension: total scores range from 0 to 100; higher scores indicate a better quality of life.
Participant timeline {13}
As shown in Fig. 3, potential participants will undergo relevant inquiries and condition assessments during the initial visit to determine eligibility for the study. Then participants will voluntarily sign an informed consent form. The initial treatment will be scheduled, with participants receiving treatment three times a week for a total of four weeks, ideally with sessions scheduled every other day. Follow-up assessments will be conducted at 2, 4, 8, and 12 weeks following the initial treatment.
Sample size {14}
In all power calculations for the study, we have assumed a 1:1 allocation ratio between the intervention and control groups. A two-sided significance level of 5% will be applied for hypothesis testing, allowing for robust statistical analysis of the study results.
The sample size assumption is based on the findings of previous studie [25] and our preliminary observation was conducted from July to September 2023. The results from Tu JF et al. (2021) demonstrated that the VAS increased by 3.52 (µc) in the regular electroacupuncture group. And in our previous observation, the VAS were enhanced by 4.53 (µr) from baseline to the end of 4-week Zha Tiao electroacupuncture treatment. The standard deviation of the ZT-EA group was found to be 1.25 (σ). Based on the provided data, with 1/3 of the standard deviation of the ZT-EA group selected for Δ, a significance level (α) of 0.025 (single-sided), corresponding to Z1-0.025 = 1.96, and a power (1 - β) of 0.90, corresponding to Z1-0.10 = 1.282, the ratio of the number of subjects between the ZT-EA group and R-EA group (K) set as 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
Considering an estimated dropout rate of 20% to account for potential participants attrition during the study, the adjustment results in a total of 78 participants available for analysis, with 39 participants allocated to both the ZT-EA group and the R-EA group.
Recruitment {15}
Recruitment posters for the study will be prominently displayed at the outpatient clinics of the Shanghai Municipal Hospital of TCM (Fig. 1). Additionally, recruitment advertisements will be strategically posted on the hospital's social media platform, official WeChat, to appeal to a wider audience and increase visibility. In addition to these strategies, researchers will actively engage with outpatients who are assessed for knee pain, personally informing them about the study and inviting them to participate.
Assignment of interventions: allocation
Sequence generation {16a}
Eligible patients will be randomly allocated in a 1:1 ratio to either the ZT-EA group or the R-EA group. The allocation will be achieved using a computer-generated random sequence through the stratified block randomization method in SAS version 9.3 (SAS Inc., Cary, NC, USA). The random sequence will be generated by the Shanghai Municipal Hospital of Traditional Chinese Medicine Clinical Research Center, an independent department ensuring the integrity and impartiality of the process.
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 research center manager. Participants, outcome assessors, and data analysts involved in the study will not have access to the contents of the randomization list.
Implementation {16c}
The research center manager will inform the acupuncturists about the patients’ randomization number and treatment group via mobile phone or WeChat.allocation concealment will not be revealed until the final outcome analysis is reported.
Assignment of interventions: Blinding
Who will be blinded {17a}
Enrolled participants will only be informed that they would receive one of the two acupuncture therapies, while the outcome assessors and data analysts, they will not aware of the treatment allocation. However, it is not possible to mask acupuncturists to their allocation due to they have to know which intervention they use for participants, but will not conduct surveys or interviews. A blinding assessment test will be used at week 4 and week 8, all participants and outcome assessors will be asked to guess which acupuncture therapy they have received.
Procedure for unblinding if needed {17b}
There will be two situations that require unblinding:
(1) When data entry and statistical analysis are completed.
(2) Participants who meet any of the withdraw criteria (As show in 11b).
Data collection and management
Plans for assessment and collection of outcomes {18a}
At the initial visit, the lead researcher will be responsible for completing the disease diagnosis, assessment, and inclusion of participants. The outcome measures, including the VAS, WOMAC, and SF-12, will be self-reported by the patients to capture their subjective experiences and perceptions of their condition. Additionally, objective assessments such as ROM, muscle’s CSA, fastest walking time of 15 meters, axial alignment of the lower extremity, and lower limb strength will be conducted by research assessors. These assessments will be conducted at baseline, week 2, 4, 8, and 12 after intervention, and recorded in the CRF. (Fig. 3)
Plans to promote participant retention and complete follow-up {18b}
The research assistants will be responsible for contacting and informing all participants regarding follow-up appointments scheduled at weeks 8 and 12 that via text message, phone call, or through the messaging platform WeChat. Finally, we will pay the transportation subsidy of patient who completes the follow-up.
Data management {19}
After completion of the trial, research data will be entered into the EpiData 3.1 electronic database for efficient management and analysis. To ensure accuracy, two independent researchers will input and cross-check the data entries, employing a double-entry method to minimize errors and maintain dataset integrity. Following the completion of statistical analysis of Shanghai Municipal Hospital of TCM Clinical Research Center, the data will be locked to prevent further modifications. Subsequently, only the senior supervisors will review and confirm the locked data, providing an additional layer of quality control. Both paper files and electronic documents containing research data will be preserved for a minimum of 5 years post-publication.
Confidentiality {27}
All personal information and research data collected during the study will be securely stored, with access limited to the lead researchers and designated research team members only. The informed consent forms and Case Report Forms (CRFs) will be stored separately from the research data in locked filing cabinets with the purpose of further enhancing security and confidentiality. It's important to note that the information collected will be used solely for the purposes of this study and will not be utilized for any other purpose without explicit consent from the participants.
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
Statistical methods for primary and secondary outcomes {20a}
Statistical analyses will be performed using SPSS 26.0 statistical software (IBM Corporation, Armonk, NY, USA). A significance level of p < 0.05 will be considered statistically significant. For normally distributed variables, the mean ± standard deviation (SD) will be reported, while for non-normally distributed variables, the median and interquartile range will be used. Categorical variables will be described as counts and percentages. Between-group mean differences and two-sided 95% confidence intervals (CIs) will be presented to assess superiority. Within-group and between-group analyses will be conducted using independent sample t-tests or Mann-Whitney U tests to compare outcomes from baseline to each time point. Additionally, repeated measures analysis of variance (ANOVA) will be employed to analyze treatment effects over time, with time (six time points: T0-T5) as the factor. For categorical variables and adverse effects between groups, chi-squared tests or Fisher’s exact tests will be used for analysis.
Interim analyses {21b}
N/A. Based on our prior clinical treatment outcomes and feedback from patients, Zha Tiao electric acupuncture has demonstrated favorable results with fewer acupoints and minimal complications. As a result, it enjoys higher acceptance among patients compared to other treatment modalities.
Methods for additional analyses (e.g. subgroup analyses) {20b}
N/A. The primary aim of this study is to evaluate the effectiveness of two acupuncture techniques for KOA and assess the feasibility of conducting a larger clinical trial.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
Intention-to-treat (ITT) analysis will be conducted following two key principles to account for protocol non-adherence. Sensitivity analyses will also be performed to assess the impact of missing data on study outcomes. Any instances of withdrawal or loss to follow-up will be thoroughly documented and clarified to ensure transparency and integrity of the study results.
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 (ChiCTR2400085328). After completion of the trial, participant data and analysis code will be accessible from the corresponding author upon reasonable request.
Oversight and monitoring
Composition of the coordinating centre and trial steering committee {5d}
Essential guidance and daily support will be offered throughout the trial by the trial steering committee, which comprises the senior supervisor and Clinical Research Center director.
Composition of the data monitoring committee, its role and reporting structure {21a}
The data monitoring committee (DMC), comprised of an orthopaedic surgeon, acupuncturist, ethicist, assistant, and statistician, will operate independently out of the study. According to the "Guiding Principles for the Data Monitoring Committees of Clinical Trials of Drugs (Trial)" issued by the National Medical Products Administration (No. 27 of 2020), the DMC will conduct biannual monitoring of potential AE and SAE, program recruitment status, participant adherence, and data integrity.
Adverse event reporting and harms {22}
At the time of inclusion, each participant was requested to provide a relative's contact information for emergency situations. Participants or their relatives are required to promptly report any adverse event (AE) and serious adverse event (SAE) to the research team. Health-related incidents will adhere to standard adverse event reporting procedures. All SAEs will be evaluated by the study leader, who will report them to the Ethics Committees (EC) and DMC for monitoring and review as necessary.
Frequency and plans for auditing trial conduct {23}
The trial will be reviewed twice a year by the EC and DMC, who are not tied to the investigators and the sponsor.
Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees) {25}
Any significant modifications to the study protocol will necessitate approval from the EC of Shanghai Municipal Hospital of TCM. Recruitment posters, registration, and informed consent will be updated accordingly If amendments impact patient procedures.
Dissemination plans {31a}
The trial findings will be disseminated through a final report and peer-reviewed publications. Upon completion of the study, participants can contact the research assistants to access their individual research reports.