Study design
This is a multicentre, blinded RCT with two parallel groups: the Tuina manipulation group and the health care education group. The research protocol was approved by the Regional Ethics Review Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine affiliated with Shanghai University of Traditional Chinese Medicine (Project No. 2019-097). It has been registered with the China Clinical Trial Registry (ChiCTR-2000030154). A total of 170 eligible patients with KOA will be randomly assigned to the two groups in a 1:1 ratio. All patients will be asked to provide written informed consent. Outcome assessments and statistical analyses will be performed by independent investigators blinded to the patient assignments. The research design is illustrated in the flow chart in Figure 1, and the research schedule is shown in Figure 2.
Participants
Eligible participants will be patients diagnosed with KOA. Patients will be notified of the trial if knee pain or dysfunction affects their daily activities at work or elsewhere. If patients express willingness to participate, the clinical trial communicator will describe the trial to them and ask them if they would like to participate. If the patient wishes to participate, an interviewer will conduct a face-to-face interview in the reception room of the hospital. Patients who meet the inclusion criteria and do not meet the exclusion criteria can join after signing the consent form.
Recruitment
We will make this trial publicly available to potential participants in the following ways: 1) posting recruitment posters in the hospital's outpatient and ward corridors; 2) posting advertisements in community centres near the hospital; 3) posting information on the hospital's official Weibo and WeChat platforms, and 4) printing advertisements in newspapers.
Inclusion criteria
Participants who meet all of the following criteria can be enrolled:
1) Fulfilment of the diagnostic criteria for knee osteoarthritis
2) Knee X-ray Kellgren and Lawrence grade 1: the joint space is possibly narrowed and may have osteophytes
3) Intensity of pain measured on the visual analogue scale (VAS) at the time of recruitment exceeding 3 points
4) Age between 40 and 65 years old, male or female
5) No massage or other related treatment received within the last 4 weeks prior to the study
6) Voluntary participation and provision of a signed informed consent form
7) Ability and willingness to comply with the interventions and follow-up assessments
8) Agreement to not receive other related treatments (including cartilage softeners) during treatment.
Exclusion criteria
Participants who meet any of the following conditions will be excluded:
1) A history of trauma and surgery in the knee or diseases such as cancer, tuberculosis, and osteomyelitis in the knee
2) Severe liver and kidney dysfunction, severe cardiovascular disease, diabetes and mental illness that could affect massage therapy
3) Inability to communicate or provide self-care due to mental or psychological disorders associated with severe mental illness or dementia
4) Physical pain caused by other diseases
5) Partial damage in the acute phase or local skin damage
6) Duration of knee joint pain or stiffness episodes less than 0.5 hours.
7) Pain attacks for less than 3 months or more than 2 years
8) Failure to adhere to treatment at the prescribed time
9) Use of massage or other related treatments within one week prior to entering the study
10) Participation in other clinical trials
11) Use of any other treatment (drug or non-drug) during the trial.
Dropout criteria
Participants who do not complete the clinical programme for the following reasons should be considered as having withdrawn from the study:
1) Patient withdrawal (poor efficacy or adverse reactions)
2) Lost to follow-up
3) Patient removal by a researcher (poor compliance, complications or serious adverse events).
The test communicator will have in-depth communication with a patient who wants to withdraw from the trial because of low effectiveness or a lack of time to promote retention.
Randomization
In this trial, the Yueyang Hospital Science and Technology Department will generate a random sequence using a random number generator (SPSS 21.0, SPSS Inc., Chicago, IL, USA). Random numbers will be placed in opaque envelopes, numbered sequentially, and sent to the therapists. The envelopes will be opened in numerical order to determine the assignment of participants during screening. After completing the baseline questionnaire, the therapist perform the physical examination and apply the exclusion criteria. Only after that has been completed will the envelope be opened, so that the study administrator, therapist, and the study participant are unaware of the group assignment until all baseline data have been collected.
Blinding
As an open-label clinical trial, both clinicians and patients will know which treatment is being administered. The clinical efficacy assessment will be conducted by the clinical assessor on the phone, and the assessor will conceal the treatment. During the data collection and analysis phase, clinical researchers, evaluators, and statisticians will not share research information with each other.
Interventions
Participants will receive 12 treatments within 4 weeks. The treatment will be carried out by a senior therapist who has studied acupuncture and massage and has been licensed for more than 10 years. Participants will be asked to rest for 15 minutes before treatment. A constant room temperature of 23 to 25°C will be maintained to ensure that the patient is comfortable and relaxed during treatment. The intervention will be performed twice a week. Each treatment will last for 20 minutes. Knee function will be assessed at baseline and 2, 4, 8, and 12 weeks after the baseline assessment.
Tuina manipulation group
In this part of the study, the therapist will use a two-step approach to relieve pain around the knee and improve knee dysfunction. The therapist will release the soft tissue around the knee by inducing general relaxation while addressing specific structural problems. The clinician will determine which approach will be most helpful for alleviating pain due to KOA and for promoting air transport (activation of blood circulation according to traditional Chinese medicine (TCM) theory). The specific scheme used will be as follows.
The specific method of massage implemented will be based on conventional acupoint tuina manipulation around the knee joint of the patient. The pain points will be identified based on the description provided by the patient and palpation of the area by the practitioner and then treated with Tuina manipulation, 20 minutes each time, 3 times a week for 4 weeks.
Step one: Check the pain points around the knee joint
With the patient in a supine position, the examiner will identify pain points by holding the upper part of the patient's knee joint in one hand while sliding and pressing the thumb of the other hand along the inner knee, the outer knee eyes, any adductor nodules, the medial and lateral joint spaces, the femur, the tibia, and the periorbital and popliteal fossa.
To check the popliteal fossa, the patient will be placed in the prone position with the knee bent, and the practitioner will slide and press the thumb along the centre, the lower portion, the outside and the upper portion of the popliteal fossa. When inspecting the inner side of the apex patellae, the examiner will push the patella downwards with the left hand so that the apex patellae is lifted up and then press the facies medialis of the apex patellae with the fingertips of the right hand, with the thumb facing upward.
Step two: Tuina local manipulation
The patient will be placed in the supine position. The doctor will stand on the affected side, apply Tuina manipulation to a regular acupuncture point around the patient's knee joint and then press and rub the patient's pain point. The pain point is generally considered to reflect the underlying condition and is often used for pain relief. The frequency of the press and rub manipulation should be 120-140 times/min. The doctors press the acupoints, including Futu (ST32), Liangqiu (ST34), Dubi (ST35), Xiguan (LR7), Neixiyan (EX-LE4), Xiyan (EX-LE5) and Ashi points, with the thumb to achieve Deqi sensation. Then, the patient will be placed in the prone position, and the doctor will repeat the above operation.
Health care education group
In the health care education group, patients with KOA will participate in a 45-minute health care educational seminar three times a week for 4 weeks. The programme will include a 30-minute lecture and a 15-minute discussion. The content will involve the diagnosis of KOA, healthy diet, pain management, physical and mental health, and healthy lifestyle factors.
Each participant will be given an introduction about the underlying mechanisms and predisposing factors of KOA. Interventionists will draw up specification of daily routines for participants, for example: Keep the knees warm; prevent obesity; maintain a beneficial posture and abandon bad exercise posture; avoid fatigue, excessive exercise or weight lifting; choose appropriate exercise; maintain a good mental state, and inform them that chronic pain has a long process.
Allowance for concurrent treatment of patients
All KOA treatments are prohibited during the trial, including oral muscle relaxants, anaesthetics, analgesics, surgery, drug injections, acupuncture and physical therapy. They may receive any treatment that is not related to knee pain. Any changes to concurrent treatments will be recorded at each visit.
Primary outcome measurements
KOOS
The knee injury and osteoarthritis outcome score (KOOS) has been widely used in research and has been shown to be efficient and reliable when use to measure knee pain [26]. We used the KOOS (0-100 scale, 0 for extreme knee problems, 100 for no problems) as our primary outcome at baseline and at the end of the intervention to measure the clinical results. The KOOS scale is an extension of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), a self-administered 42-question survey covering five patient-related domains: pain, other disease-specific symptoms, daily functional activities, motor and recreational functions, and knee-related quality of life. The scale is an effective, reliable, and responsive method of measuring results with good test reliability and structural validity for total joint replacement. We used other KOOS subscale scores as the primary outcome. We will measure the outcome at these five time points (baseline, two, four, eight and twelve weeks) and compare. In this trial, we will compare the mean and standard deviation of the two groups at each time point. then, the change in values from baseline until the time point will be included in the comparison.
Secondary outcome measurements
MPQ
The McGill pain questionnaire (MPQ) is a very common scale that measures and evaluates various pain [27-28]. The MPQ contains 4 groups of 20 pain descriptions. Each group of words is arranged in increasing order with regard to the severity of pain. Dimensions one to ten are sensory, 11 to 15 are affective components of pain, 16 are pain evaluations, and 17 to 20 are miscellaneous. The test subject selects a word to indicate the degree of pain in each group (they must select a word).
SF-36
The SF-36 questionnaire assesses the association between health-related quality of life and various factors [29]. It is widely used in the field of quality of life, clinical trials and health policy. It consists of 36 questions, divided into Physical Functioning (PF), Role-Physical (RP), Bodily Pain (BP): General Health (GH), Vitality, Social Function (SF), Role-Emotional, (RE), Mental Health (MH), General Health (GH) and eight other aspects. For each domain, the score ranges from 0 to 100, with higher scores reflecting a better quality of life. The SF-36 will be evaluated using repeated longitudinal analysis. Same as primary outcome, secondary outcome will be measured at these five different time points (baseline, two, four, eight and twelve weeks).the method of aggregation and the metric for comparison is the same as KOOS.
Safety evaluation
Treatment safety will be assessed by researchers monitoring patient symptoms before and after treatment. In this trial, the following events will be defined as adverse events (AEs): (1) severe pain; (2) syncope; (3) deterioration in walking function; (4) hospitalization; and (5) life-threatening changes, all of which will be carefully recorded in the case report form. In the case of any AEs, whether or not they are related to the treatment, treatment will be stopped immediately. The patient will be treated, and the AEs will be reported to the responsible unit and the ethics committee to determine if the patient should withdraw from treatment.
Follow-up
To assess the short-term efficacy, long-term efficacy, and safety of the interventions, we will track participants for 2 months after the trial. During the 2 months of unsupervised follow-up, no participants will receive special treatment other than regular knee care. At weeks 8 and 12, the evaluators will investigate the recurrence of knee pain over the telephone. Patients will also be able inform the assessor of their clinical signs and mood changes by email, text message or WeChat at the relevant time. During the follow-up period after the trial, any health issues will be assessed, and the committee will be notified.
Data collection and monitoring
The assessor will record the clinical results in the case report form (CRF), including the assessment of the treatment effect, the changes in physiological function and details of AEs. The completed CRFs will be reviewed by a four-person steering committee composed of the heads of the four research centres. Then, the CRFs will be submitted to the data stewards, who are independent of the research team and do not know the group allocation of the participants. The stewards will enter the data into an Excel database. All data administrators will have data analysis qualifications and unified training. To ensure the accuracy of the data, the two data administrators will independently enter the information and check the accuracy of the entered data. If there is a problem with the information on a CRF, the data administrator will complete the requisite form, and then the data administrator can modify the data according to any revisions provided by the steering committee. After confirming that the database is correct, the steering committee, data stewards, and statisticians will lock the database.
Health economics
All costs associated with this test will be recorded. These costs mainly include medical costs for the direct treatment of KOA, such as inpatient bed fees, outpatient registration fees, Tuina treatment fees, daily care and testing fees, and in addition, the cost of treatment for any AE will be recorded and included in the health cost evaluations.
Sample size calculation
The expected efficacy rate of Tuina manipulation is 70%, and the efficacy rate of health care education based on the literature is 45%. The sample size was calculated with a significance level of 0.05 and power of 0.90, with consideration of a maximum dropout tolerance of 10%. Finally, 170 patients are needed for the trial, with 85 patients in each group.
Data analysis
Demographic and baseline data will be analysed with standard descriptive statistics. Between-group differences will be tested using repeated measures analysis of variance. The acceptable significance level for all analyses will be P<0.05. The complete analysis set, including dropouts, will be analyzed through an intention-to-treat (ITT) population analysis. Statisticians who are independent of the research team and are blinded to group allocation will perform the data analysis. Data analysis will be performed with SPSS software (for Microsoft Windows® SPSS, Inc., SPSS 21.0 KO, Chicago, Illinois, USA).
Quality control
To improve the reliability of the results of this study, we designed quality control procedures with regard to the following aspects: (1) baseline homogeneity: this study limits the age of participants to between 40 and 65 years, and we will assess people with similar living habits; (2) Tuina manipulation: in this study, all researchers will be trained to fully understand the design and protocol of the trial, the use of the CRF, and the manipulation technique. To avoid operational differences, two experienced doctors who will have received specialized standardized training before the trial will perform all treatments in accordance with the standard operating procedures. In addition, during the treatment, except for that needed to identify pain points, communication between the therapist and the patient is prohibited; (3) Pain points: considering the importance of pain point identification for accurate treatment evaluation, the pain threshold at the tender points will be measured after each treatment to evaluate whether there is a significant difference in stimulus and pain perception after each treatment, which will help rule out the bias of using the pain points; (4) data collection and completeness: Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Data Monitoring Team will be responsible for controlling bias and identifying problems in the project. Detailed records of changes will be kept. Meanwhile, a qualified clinical trial expert will monitor the therapists after every course of treatment, and regular board meetings will be held to ensure the quality of the study process.