Evaluation of the effect of low-intensity pulsed ultrasound in pain and dysfunction for knee osteoarthritis: a double-blind, randomised controlled trial protocol

Study design

This randomised, double-blind, controlled trial will be performed at the Rehabilitation Center of the Shengjing Hospital, China Medical University. The study protocol was approved by the ethics committee of Shengjing Hospital of China Medical University (2023PS592K) and registered in the Chinese Clinical Trial Registry (ChiCTR2300069643; registration date: 22 March 2023).26 The study adheres to the following standardised guidelines for reporting clinical trials: the Standard Protocol Items: Recommendations for Interventional Trials guidelines and the clinical trial recommendations from the Osteoarthritis Research Society International (OARSI).27 28 A Consolidated Standards of Reporting Trials flowchart related to the stages of the study is shown in figure 1.

Figure 1

Flowchart of the research process according to the randomised trial synthesis criteria. LIPUS, low-intensity pulsed ultrasound.

Patient and public involvement

Neither patients nor the public participate in the planning, execution, documentation or dissemination of our research.

Participants

Patients with symptomatic KOA will be enrolled. Recruitment information will be disseminated through various channels including WeChat, public websites, media and posters in the rehabilitation department and orthopaedic clinics of Shengjing Hospital that are affiliated with China Medical University. Prior to randomisation, the rehabilitation physician will conduct an initial screening of potential participants (eg, age, co-existing symptoms, etc) by telephone and determine the time of the visit.

Standardised bilateral weight-bearing semiflexed radiographs will be performed prior to enrolment to assess eligibility. Patients will be positioned with both knees at 20°–30° of flexion and 10° of foot pronation during imaging.29 Radiographs will be graded independently by two physicians with more than 10 years of experience in OA management to determine the Kellgren-Lawrence (KL) grades.30 Any grading discrepancies will be resolved by consensus discussion or evaluation by a third senior practitioner if needed. Eligible patients will then be scheduled for a visit to confirm their eligibility, provide written informed consent and be assigned a participant identification number. Signed informed consent documents will be retained in the study records.

The inclusion criteria are as follows: patients with KOA aged≥38 years, with a confirmed imaging diagnosis (KL grade I–IV),31 who meet Altman’s clinical diagnostic criteria for KOA,32 who are able to communicate and understand Chinese characters in Mandarin, who can fully comprehend the content of the rating scales and who can sign the informed consent form alone (online supplemental material).

The exclusion criteria were as follows: recent acute knee injury; rheumatoid arthritis or other types of arthritis, gout, ankylosing spondylitis or severe osteoporosis; history of treatment with intra-articular injections (hyaluronic acid or corticosteroids) or physiotherapy within 6 months prior to enrolment; MRI showed KOA with more than moderate joint effusion or III degree meniscus injury; diagnosis or suspicion of other conditions limiting mobility including cerebrovascular disease, hepatic dysfunction, cardiopulmonary insufficiency, pacemaker implantation or systemic diseases that could potentially affect joint function; lower extremity vascular disease, neurological deficits or physical deformities; contraindications for MRI; contraindications for ultrasound therapy such as coagulation abnormalities, lower extremity deep vein thrombosis, peripheral tumour or infection, or metallic implants; severe psychiatric illness, cognitive impairment, poor compliance or inability to tolerate testing procedures; pregnancy, as ultrasound therapy and MRI scanning may pose risks to the fetus; and inability to provide informed consent.

Randomisation and blinding

An independent researcher with no role in the assessment or intervention will execute block randomisation in this study using SPSS V.28.0 statistical software. Before the commencement of the study, a random sequence generator was used to create four different randomly permuted blocks. Each block represented a unique grouping of participants for either the LIPUS treatment group or the placebo ultrasound group. The ratio of participants assigned to each group was maintained at 1:1 to ensure balance. To conceal randomisation, consecutively numbered, sealed, opaque envelopes will be centrally prepared and kept by an independent staff member in a location accessible only to the research administrator.

A double-blind approach will be used, in which participants will be blinded to their group allocation and intervention. To maintain blinding, a sham ultrasound will be administered to the control group using identical equipment and protocols as the treatment group. During the informed consent process, the participants will be fully informed about the treatment options and both intervention arms will be considered standard care with evidentiary support. Physical therapists will undergo standardised training prior to the commencement of the study and will be randomly assigned to one treatment group for the duration of the trial. All data collectors, manual therapists, statisticians and outcome assessors will be blinded to the group allocation. When administering the questionnaires, the participants will be instructed not to discuss their treatment during the assessment period.

If an adverse event occurs during the trial, the clinician will report it to the principal investigator, who will determine whether unblinding is warranted. If unblinding is deemed necessary, the principal investigator will access the participants’ allocation and notify the supervising physician. However, the supervising physician must not disclose the unblinded treatment assignment to other study personnel or participants.

Interventions

Once participants are enrolled, they will be provided with a treatment manual and oriented towards the study procedures by a blinded rehabilitation physician. Baseline data will then be collected, including demographics (such as height, weight, knee injury and pain history, previous medications and treatments) and patient-reported outcomes (Western Ontario University and McMaster University Osteoarthritis Index (WOMAC) and Lequesne scales). Subsequently, participants will undergo functional assessments (time up and go (TUAG) and range of motion (ROM)) and pain intensity ratings using Numerical Analog Pain Rating Scale (NPRS). The order of functional and pain assessments will be randomised.

After baseline data collection, all the participants will receive 10 treatment sessions. Each session will last 45–60 min, and the interventions will be administered by nine physical therapists with a minimum of 5 years of relevant clinical experience. The selection of warm-up modalities will be based on individual participant presentations after initial intake (online supplemental table 1).

When warm-up finalises, participants will be placed in a supine position with the affected knee flexed at 90°. The treatment area will be inspected for skin abnormalities, including rashes, infections and open wounds. Target sites for therapeutic ultrasonography will include the suprapatellar, infrapatellar and medial collateral ligaments; medial tibiofemoral articular subchondral bone; lateral collateral ligament; and lateral tibiofemoral articular subchondral bone. Ultrasound will be delivered using a 4 cm/s moving technique with hydrogel as the coupling agent. Care will be taken to ensure adequate acoustic contact and a 90° angle of insonation perpendicular to the treatment area to maximise energy absorption.

The treatment group will use a probe area of 5 cm² (XY-K-CSB-I Ultrasound Therapy Apparatus (Xiangyu Medical Equipment, Guangzhou, China)) with a frequency of 1 MHz, pulse ultrasonic power of 1 W/cm², duty ratio of 20%, effective radiation area of 10 cm², conveying for 10 min. The control group will use the same ultrasound equipment as the treatment group; however, the same treatment schemes (using a silent head crystal) will be false. After ultrasound treatment, the equipment will be returned to zero, the ultrasound probe gel will be cleaned, the treatment site will be examined and patient feedback will be recorded. Afterwards, 8–10 min of treatment site manipulation (online supplemental table 1) will be performed to increase joint activity.

At the end of each session, therapists will complete a ‘Treatment Notes’ form (online supplemental table 2) to document all interventions performed. The treatments will be administered once daily for 10 sessions. The participants will be asked to refrain from additional treatments during the trial period; however, analgesics and non-steroidal anti-inflammatory medications will be permitted. The type, dose, frequency and duration of medication use will be recorded in detail in the treatment description form.

Outcome measures

The trial outcomes were selected based on the recommendations of the International Society for the Study of Osteoarthritis Working Group.33 Outcomes will be assessed at baseline (T0), after 10 treatment appointments (T1) and 1 month after the conclusion of the intervention (T2). All outcome assessments at each time point will be conducted by the same rehabilitation physician who was trained and standardised to evaluate all participants consistently. The study schedule is presented in table 1.

Primary outcomes

WOMAC: the WOMAC Scale is a clinical tool specifically designed to assess the health status of patients with hip and KOA and is used to quantify OA symptoms. A total of 24 questions are divided in three categories assessing pain, stiffness and physical function.34 35 Evaluation using the Likert method will be as follows: none=0, mild=1, moderate=2, severe=3 and very severe=4. The total score on a 0–96 scale will reflect the severity, with higher numbers indicating more intense pain, stiffness and physical dysfunction. WOMAC can be completed in a short time, and its reliability and sensitivity have been proven in different languages, with a scale test–retest reliability of 0.83 and a convergent validity of 0.77.36–38 As it is a self-administered measurement, the participants will complete the measurements themselves. The study personnel will not be allowed to assist the participant to answer any of the questions; however, they will be required to check that all the questions have been completed before the patients complete all the assessments.

Secondary outcomes

NPRS: the NPRS is a single-dimensional method of measuring pain intensity. It is an 11-point numerical scale ranging from 0 to 10, with 0 representing no pain and 10 representing the worst pain imaginable.39 40 The sensitivity of the NPRS as an indicator of early symptomatic OA has been demonstrated, with a minimum clinical important difference of 1.8.41 42 In this study, respondents will be asked to report their pain intensity ‘in the past week’, which can be reflected in integers (0–10 integers).

Lequesne Scale: this scale is used to evaluate pain, walking ability and daily activities in patients with OA. It consists of three subscales with a total of 11 items. The scores on the pain and daily life subscale range from 0 (no pain or functional limitations) to 8 (extreme pain or functional limitations). Walking ability is rated from 0 (greater than 1000 m) to 6 (less than 100 m) on the walking ability evaluation subscale. For patients who need an auxiliary tool, such as a crutch, the score is increased by 1 min per auxiliary tool (if the patient needs two crutches, the score is increased by two points). Overall scores range from 0 to 24. A score of <7 points is considered mild to moderate, 8–13 points severe and 14–24 points very severe.43

TUAG test: this test is a method to evaluate the functional mobility of patients with KOA. This index is used to follow the recommendations of the OARSI.44 The time required for the patient to get up from the seat, walk 3 m, return to where he/she started, turn around, return to the chair and sit down is recorded.45 Three repeated measurements are performed, and the mean is recorded in ‘seconds’, with an accuracy of 0.1 s.

ROM of the knee: According to the method of Marques, a generic goniometer is used to measure knee flexion range. The patient is placed in the supine position with the thighs relaxed and knees bent. The fixed-angle measuring arm is placed at the femoral lateral surface, pointing to the large rotor and moving the arm parallel to the side of the fibula to the external ankle. Any additional hip movements, such as rotation, extension or flexion, should be avoided. The measurement is repeated three times, and the average of the measurements is kept accurate to 1°.

Sample size

The required sample size was analysed using the pwr package of R software (V.4.3.1, R Foundation, Vienna, Austria). There was a prespecified moderate effect size f=0.25, power 1−β=0.8 and significance level α=0.05. The results showed that at least 78 subjects were required for each group. Assuming a 20% dropout rate, we planned to enrol 200 patients and randomly assign them to the treatment group or the control group.

Withdrawal and adverse events

When a participant withdraws from the study, the responsible physician should try their best to contact the participant by phone or letter to inquire about the reason for withdrawal. The reason for withdrawal should be documented carefully, along with the date of the last treatment session completed and any evaluable data collected up to the withdrawal date. Participants who complete more than half of the planned treatment sessions before withdrawal will be included in the efficacy analysis. Those who withdraw due to adverse events after less than half of the planned sessions will be considered non-evaluable for efficacy, but will be included in the safety analysis. Any adverse events encountered will be documented in the case report form (online supplemental table 3) and reported with the study results. All exclusions and withdrawals will be accounted for in an intention-to-treat analysis after study completion.

Statistical analysis

An intention-to-treat analysis will be used. All analyses will be performed using SPSS V.28.0. Continuous variables (eg, age and body mass index) will be presented as mean±SD and compared between groups using independent sample t-tests. Categorical variables will be presented as percentages and compared between groups using χ² tests. For repeated measures data that meet the normality and homogeneity of variance assumptions, repeated measures analysis of variance(ANOVA) will be used. For non-normal or heterogeneous data, the Kruskal-Wallis H test will be used for between-group comparisons. The Wilcoxon signed-rank test will be used to evaluate the pre changes and post changes within each group. The Lequesne and WOMAC scales will be analysed using non-parametric methods.

Data management and monitoring

To protect privacy, the participants will be assigned numeric codes after recruitment to replace their names. Data will be collected at baseline, after the 10th treatment session and at the 1-month follow-up. All data will be double entered after proofreading by two rehabilitation physicians and will be stored electronically to prevent erroneous data entry. Printed files will also be kept. All paper documents and electronic files related to the study will be securely kept by the research team with scheduled backups. Following the completion of the clinical trial, all trial-related data will be securely retained for a minimum of 5 years to ensure data traceability and auditability and to comply with relevant regulations and policies. On expiration of the data retention period, a data destruction process will be initiated. Data destruction will adhere to applicable data protection and privacy regulations and will involve complete physical erasure and logical deletion of the data from storage media.

Ethics approval and dissemination

The study protocol was approved by the ethics committee of Shengjing Hospital of China Medical University (2023PS592K). All eligible patients will be informed about the interventions and the adverse events prior to signing the consent form. All patients’ data will be archived in a unique confidential manner at all stages of the trial and also this confidentiality will be protected during and after the trial. The results will be submitted to specialised peer-reviewed journals and scientific meetings.