Effect of Acupotomy in Knee Osteoarthritis Patients: Study Protocol for A Randomized Controlled Trial

Effect of Acupotomy in Knee Osteoarthritis Patients: Study Protocol for A Randomized Controlled Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Effect of Acupotomy in Knee Osteoarthritis Patients: Study Protocol for A Randomized Controlled Trial Danghan Xu, Minghui Lee, Cihui Huang, Jia Wei, Mengxue Zhou, Taotao Yao, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-35085/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Apr, 2021 Read the published version in Trials → Version 1 posted 13 You are reading this latest preprint version Abstract Background Symptomatic knee osteoarthritis patients are common in China. Pharmacologic therapy is not the first recommendation because of its safety issues. Non-pharmacologic therapy, such as lifestyle adjustments, weight loss, and proper exercise is strongly recommended to use in knee osteoarthritis. But the adherance rate is very poor. Acupotomy therapy, as an effective treatment for knee osteoarthritis, is lack of high quality randomized controlled trials. This study set out to investigate the efficacy of acupotomy in patients with knee osteoarthritis. Methods 136 patients will be enrolled in the First Affiliated Hospital of Guangzhou University of Chinese Medicine, and assigned into acupotomy group or sham acupotomy group according to the block randomization number. The acupotomy group will receive 2 sessions of acupotomy for 2 weeks(once a week). The sham group will receive 2 sessions of sham stimulation for 2 weeks༈once 2 week. All the patients will use indomethacin cream externally. The primary outcome is the WOMAC index and the secondary outcomes are VAS, plantar pressure distribution test, X-ray examination, musculoskeletal ultrasound, maximum knee circumference, and joint mobility. We will measure them at baseline, one week after the end of treatments, the third month and sixth month follow up. Discussion As we know, this is the first single-blinding and sham controlled design in acupotomy research. We aim to prove the efficacy of acupotomy in treating knee osteoarthritis. Trial registration Chinese Clinical Trial Registry: ChiCTR2000033047(2020-5-18). Translational Medicine Internal Medicine Integrative & Complementary Medicine acupotomy needle-knife knee osteoarthritis study protocol randomized controlled trial Figures Figure 1 Figure 2 Background As the 11th highest contributor to global disability, knee osteoarthritis (KOA) triggers burdensome pressure for society and family [ 1 ] . In China, symptomatic knee osteoarthritis patients are common [ 2 ] . Symptomatic knee osteoarthritis will cause pain and impaired knee function. 3.9% of knee osteoarthritis patients are suffering from these severe torments, which leads them to disability easily [ 3 ] . The pharmacologic therapy is not recommended because of its limited efficacy and safety issues [ 4 ] . Non-pharmacologic therapy has been used a lot in treating knee osteoarthritis [ 5 ] . For instence, Lifestyle adjustments, weight loss, and proper exercise are the first line recommended methods [ 6 ] . However, patients with these treatments usually have poorer adherence [ 7 ] . Thus, we are seeking for an effective non-drug therapy with better adherence to treat knee osteoarthritis. Acupotomy therapy is a special technique of acutherapy. Unlike standard acupuncture needles, acupotomy therapy will use a needle-knife with a thicker diameter and flat needle. This needle-knife can enter deep tissues to loosen adhesion. Acupotomy therapy has been used to treat knee osteoarthritis for many years, because of its longer treatment session and satisfying effect in clinical practice. Although previous studies [ 8 – 10 ] have showed the efficacy of acupotomy therapy, there is no high-quality clinical research in this field. The sloppy designs of past studies are detrimental to the power of their conclusion. Therefore, we design a randomized, single blinding, sham controlled trials to explore the efficacy of acupotomy therapy in treating knee osteoarthritis patients. Methods Study Design Based on the Declaration of Helsinki, we will design a parallel, block randomization, single-blinding, sham controlled trials. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 1). This study will be performed in the First Affiliated Hospital of Guangzhou University of Chinese Medicine from June 2020 to June 2023 (Figure 1). We will recruit volunteers via advertising, posters and contacting community doctors, and enroll those who meet inclusion criteria. Fig. 1 Flowchart of the study design. Inclusion Criteria (1) Patients meeting the I, II, and III levels of Kellgren-Lawrecne's radiological diagnostic criteria [11] ; (2) The score of pain visual analog scale is above 4 points in the past month; (3) Age is between 40-70 years old; (4) Those who have not taken other related treatment drugs or adopted related treatment methods within 2 weeks; (5) Participate should provide informed consent. Exclusion Criteria (1) Pregnant or lactating women, or women with a pregnancy plan during the trial; (2) Patients with infectious diseases or serious diseases, such as cardiovascular, cerebrovascular, liver, kidney, hematopoietic system; (3) Patients with local infection, ulceration, vascular nerve damage or deep abscess in the knee joint; (4) Patients with a history of severe knee trauma, or who have undergone surgery or arthroscopy; (5) Patients with other diseases that cause knee pain, such as tumors, knee joint tuberculosis, rheumatoid arthritis, gouty arthritis, etc.; (6) Patients who have taken oral corticosteroids or received intra-articular knee injection treatment within 1 month; or have participated in other clinical trials within 3 months; (7) People who are allergic to the medical devices involved in this trial; contraindications to the use of indomethacin plaster, such as those with a history of allergy to indomethacin, those with liver and kidney dysfunction (alanine aminotransferase (ALT), aspart The amino acid transaminase (AST) is more than 2 times the normal value, and the blood creatinine (cr) is more than the normal value). Patients who have induced asthma, urticaria or allergic reactions after taking aspirin or other non-steroidal anti-inflammatory drugs may have nonsteroidal Patients with a history of gastrointestinal bleeding or perforation after anti-inflammatory drugs, patients with active gastrointestinal ulcer bleeding, or patients with previous recurrent ulcers / bleeds, patients with severe heart failure, perioperative coronary artery bypass surgery, etc. ; (8) Patients with bleeding tendency, such as long-term use of warfarin, aspirin and other anticoagulants; (9) People with an abuse history of sedative hypnotics, opioid analgesics, and alcohol; (10) Patients who cannot cooperate with relevant experiments and measurements. Intervention Acupotomy group The patients are in a supine position with the knee flexed 30 ~ 45 °. A cushion is placed below the knee. The physicians will select 6 points from a point set as follow. The point set contains 8 points, including the upper point and lower point medial collateral ligament of the affected knee joint, the upper point and lower point lateral collateral ligament, the subpatellar ligament points, the upper point of the patella, the muscle insertion of the popliteal muscle, and the medial popliteal fossa stimulation points. We will stimulate 6 points for unilateral knee pain and 12 points for bilateral knee pain (Table 1). After standard disinfection, the physicians will operate Hanzhang Ⅰ type No.4 straight needle knife (Beijing Huaxia Needle Knife Medical Equipment Factory) to run acupotomy therapy (Figure 2). All these physicians have more than 5 years of acupotomy experience and will be retrained 16 hours before the study begins. The incision line is consistent with the longitudinal axis of the lower limb. The body of needle-knife is perpendicular to the skin. The doctor operates according to the procedures of fixed point, orientation, pressure and penetration. When the needle knife reaches the target depth, the doctors perform a manual operation. After the operation, the needle-knife is pulled out, and local hemostasis is applied for 3 minutes. The wound was disinfected with iodine and the needle eye was covered with a band-aid. Patients receive acupotomy therapy 2 sessions for 2 weeks（once a week）. Table 1. the location of point set Fig 2. the needle-knife Sham acupotomy group Patients assigned to sham acupotomy group will receive the mock acupotomy, which will be performed just like real acupotomy, but without manual stimulation to achieve any real effect. The needle-knife will pierce through the skin only and stay under the skin for 10 seconds to simulate manipulation time. Patients will receive 2 sessions of sham acupotomy for 2 weeks（once a week）. All the patients of two groups are allowed to use drugs. Clinicians will give patients indomethacin cream (manufacturer: Nipro Pharma Corporation Saitama Site Plant 2, import drug registration number H20181060) for external use, once daily after 24 hours of acupotomy. They will receive indomethacin cream 12 times in total. Outcome Measurement We had selected both clinical outcomes and surrogate outcomes to assess the efficacy of acupotomy. All the outcomes will be measured at baseline and one week after the end of treatment. Besides, we will follow up for WOMAC index and VAS in the 3 rd month and 6 th month after the end of treatment (Table 2). Before the study begins, we will train the related investigators. Table 2. Study schedules. T1-T3: from the first treatment period to the third treatment period. W7: one week after the whole treatment period; M3: the 3th month; M6: the 6th month Primary Outcome Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) The WOMAC index is always used to assess knee osteoarthritis symptoms [12] . The scale includes 24 items in three parts, including 5 pain items, 2 stiff items, and 17 joint function items. The scoring record uses a 10cm long visual analog scale scoring rule. The two ends are 0-point and 10-point. 0 points indicate that the item is asymptomatic, and 10 points indicates the most serious degree of the item. Secondary Outcome Visual Analog Scale (VAS) VAS scale is a commonly used scale to reflect the degree of body pain [13] . A 10 cm length VAS scale will be used. The two ends are 0-point and 10-point respectively. The 0 presents painless and 10 shows the most severe pain which is intolerable. Plantar Pressure Distribution Tests Plantar pressure distribution tests can observe the function of patients' knee joints [14] . This test uses the Plantar Pressure Distribution Test System (Belgium RSscan Footsacn1.0m). A rehabilitation technician will in charge of measurement. We will collect balanceparameters (foot angle and subtalar joint mobility) to assess the stability of knee joint medial and lateral. The bigger balance parameters indicate the worse stability. Besides, impulse parameters, known as the ratio of the heel and forefoot, will be used to analyze knee buffering stability. The larger the ratio, the stronger the stability. X-ray examination Interrogation of the results of the patient's front and lateral knee X-rays was performed by an imaging physician. This measurement aims to monitor whether there are existences of osteophyte formation, joint space narrowing, subchondral sclerosis, cartilage degeneration, osteoporosis, valgus deformity, and varus deformity. Musculoskeletal Ultrasound Ultrasonography has also been proven as a useful tool in monitoring knee osteoarthritis treatment effectiveness [15] . Specialized ultrasound doctors will collect data via Philip HP SONOS 5500 ultrasound imaging machine. We will pay attention to the knee joint fluid volume and synovial film thickness. These data will show us the degree of damage and repair of knee. Maximum Knee Circumference This indicator is used to assess the soft tissue lesions around the knee joint [16] . When conducting the assessment, the patients will be asked to lie supine with the knee joint straight. The doctor will use a soft ruler to measure the circumference of the knee joint along the upper and lower pole of the patella, of the metatarsal bone, and measure around the knee joint. Joint Mobility Joint mobility is also used to check knee function [17] . The arthrometer will be used to measure knee mobility. The patient being tested is positioned on his/her side with the affected leg being measured facing upwards. First, the lateral femoral condyle is positioned over the center of rotation of the arthrometer. Then position the fixed arm along the middle of the femoral joint, and fix the movable arm along the fibula. Lastly, let the patient extend the knee joint as much as possible, and then bend the knee as much as possible, and measure the flexion and extension motion range by moving the movable arm. Sample Size Referring to a previous study [18] , we determined that the change in the WOMAC index before and after treatment in the acupotomy group was 16.34 ± 4.19. Then the change in the WOMAC index before and after treatment in the sham acupotomy group was 14.2 ± 4.19, and the effect size was 2.14 [19] . The sample sizes should provide 80% of statistical power and significance level of 0.05. We calculated the sample sizes of 124 with repeated measurement design via the SAS software package (version 9.4, Tokyo, Japan). Considering the 10% loss of patients during the research, we had decided to enroll 136 participants finally. Randomization A biostatistician will generate a block random number list at a ratio of 1: 1via Stata 14.0 software package. The block size is not discovered until study finishing because of allocation concealment. An independent staff, who does not take part in the performance period of this study, will seal the random number by the opaque envelopes. Then the primary investigator will save these envelopes and open one of them when a participant is enrolled. Blinding This study takes a single-blind approach. The operators will mock the procedure of standard acupotomy therapy in the sham acupotomy group. The operators pierce through the skin only and do not stimulate the relevant ligaments and muscles. The needle-knife will stay under the skin for 10 seconds without any manipulation. At the same time, this experiment will blind other folks (data administrators, biostatisticians, programmers, measurement evaluators, etc.) to minimize performance bias. For the sake of protecting the rights of the subjects, we will approve free acupotomy treatment for the sham acupotomy group at the end of the trial. Date Management and Monitor We will train all the staff to ensure data quality. The researchers will fill the data in the Case Report Forms (CRF) and sign it. CRF does not allow alteration directly. The researchers must report to the primary investigator if they need to alter the CRF. Any changes in CRF need to be signed and dated. Data administrators will enter data into the computer. The CRF and the computer will be locked in the research center, while the primary investigator keeps the key only. The original data will be kept in the research center rather than publish. The data can be access through research center if someone applies with reasons. The data monitoring and management committee is composed of the Scientific Research Department of the First Affiliated Hospital of Guangzhou University of Chinese Medicine. They independently review and monitor research data. The South China Acupuncture Research Center Clinical Sub-center will form a quality monitoring committee. These committees will visit our clinical research center every 6 months to review and monitor the trial. The study group will run a conference to review this trial every month. Safety Monitor Acupotomy therapy may trigger adverse events including dizziness and local hematoma. When dizziness occurs during treatment, the doctor should stop the treatment immediately. Then the doctor will lay down on the pillow, and take warm water to take the service. If hematoma remains after treatment, the patient will apply a local cold compress, and switch to a hot compress at 24 hours to promote the dissipation and absorption of blood stasis. If an adverse drug reaction occurs, the drug should be discontinued. Active clinical observation and symptomatic treatment should be carried out. Ethics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine will monitor the safety of this trial and furnish us with advices (e.g., endpoint adjustment) if it is necessary. When an adverse event occurs in a patient, the researchers should record the detail, such as time, severity, duration, treatment measures, and event outcomes. The responsible doctor will determine the causal relationship between the treatment method and the adverse event, and decide to continue or terminate the study. Relevant information must be reported to the ethics committee on the same day. The following are the criteria for terminating the study: (1) the subject has a serious adverse event or the subject has requested to suspend participation in the trial, or the trial operator believes that it is necessary for the subject to suspend the trial;(2) during the study, the subject is found to have a systemic disease that could not be detected before the start of the clinical trial;(3) for other reasons, researchers believe that patients are not suitable for continued treatment;(4) patients receive privately other interventions that may affect outcomes. Statistics Analysis Per-protocol subjects’ analysis and intention-to-treat analysis were used to analyze the efficacy. The safety analysis set is used to analyze the safety evaluation. We will develop a statistical analysis plan with a statistician. The statistician R 3.4.3 software package is used to performs descriptive statistics, exploratory analysis and dropout analysis. The result is statistically significant when the P-value is less than 0.05. In the intention-to-treat analysis, when the data is missing, the last observation is used for interpolation. Then we will select sensitive analysis for the result. For continuous variables that obey normal distribution and meet homogeneity of variance, we will use Student’s t-test. if continuous variables cannot meet the condition mentioned above, the Mann-Whitney test or Wilcoxon test will be used. A chi-square test will be performed for discrete or categorical variables. When analyzing data from repeated measurements, we will use analysis of variance or analysis of covariance. For safety analysis, we will use descriptive analysis at first. Subsequently, the incidence of adverse reactions between the two groups will be compared. The causality for the severity of adverse reactions and the needle-knife operation should be considered in the comparison. If there are a large number of adverse reactions, the relationship with the intervention time and baseline characteristics should be analyzed. Discussion Knee osteoarthritis is a chronic disease with pain, swelling, stiffness, restricted movement, popping or deformity [20] . It is associated with gender, age, body weight, physical activity, occupation and biochemical factors etc [21] . There are three views of knee osteoarthritis pathological mechanism [22] . First of all, mechanical loading causes changes in biological stress, which can damage knee cartilage. Furthermore, synovial inflammation induces cartilage to secrete too much matrix metalloproteinase, which can damage knee cartilage. In addition, some adipokines, such as leptin and adipsin, are known as one of the pathological mechanisms in triggering cartilage impaired. Different guidelines had provided different suggestions of clinical practice in knee osteoarthritis [23] . The physicians always use paracetamol (acetaminophen) and NSAIDs (celecoxib, indomethacin, etc. ) to deal with knee osteoarthritis problems according to the guidelines [4, 24-26] . But patients cannot use these drugs for long time. Paracetamol (acetaminophen) does a little work for patients’ pain and stiffness and physical function [27] . Besides, paracetamol (acetaminophen) brings hepatotoxicity [28] and induces adverse reactions in kidney, cardiovascular and gastrointestinal tract with a long-term use [29] . NSAIDs will increase the risks of adverse cardiovascular outcomes [30] and upper gastrointestinal complications [31] . Hence, non- pharmacologic therapies play an essential role in knee osteoarthritis treatment [32] . Traditional Chinese Medicine can also make a contribution in this field, such as acupuncture [33] , moxibustion [34] , Taiichi and massage [35] . Compared with other non-drug therapies, acupotomy therapy is a better choice for the treatment of knee osteoarthritis. It is less frequent, which is good for persistence. Besides, acupotomy not only can relief pain but also improve patients’ joint mobility. As a special type of acutherapy, acupotomy therapy can improve knee osteoarthritis symptoms via different pathways. Knee biomechanical will be restored by acupotomy due to its function of biological street adjustment [36] . Acupotomy can also curb inflammation [37-38] . The reduction of IL-1β, IL-6, and TNF-α suppress the expression of MMP-1, MMP-3, and MMP-13, which is conducive to knee cartilage. In a word, acupotomy therapy promotes chondrocyte repair and regulate cartilage metabolism [39] . The clinical research confirmed acupotomy effect of knee osteoarthritis [9-10] . However, the study designs of the trials are both inadequate. They both selected acupuncture as a comparison, which fail to demonstrate acupotomy efficacy powerfully. One used inappropriate randomization procedures and didn’t use blinding. While another had a small sample size and used scale as outcome only. Thus, we had designed a stricter study to explore the efficacy and safety of acupotomy in knee osteoarthritis. We had selected sham acupotomy as a comparison. Besides, as we know, this program is the first single-blinding design in acupotomy research. Moreover, we will use clinical outcomes (the WOMAC index, the visual analog scale, and joint mobility) and surrogate outcomes (musculoskeletal ultrasound, X-ray examination, plantar pressure distribution test, maximum knee circumference) at the same time. This study has some limitation. Firstly, we will enroll the early and mid-term patients only, thus we cannot observe the effect of acupotomy in the late-period patients. Secondly, the long-term effect cannot be monitored owing to 6 months follow-up. Lastly, this study will be performed in China so the conclusion may not suitable for other races. To summary, we will perform a parallel, block randomized, single-blinding, sham acupotomy controlled trial to scrutinize the efficacy and safety of acupotomy in knee osteoarthritis patients. Abbreviations KOA, Knee Osteoarthritis WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index VAS, Visual Analog Scale CRF, Case Report Form Declarations Trial status This study had be performed since June 2020. The study protocol is vision 3.0 (2020.4.27). We are recruiting participants from June 1, 2020, to June 30, 2022. Ethics approval and consent to participate This trial had been approved by the ethical committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (No. ZYYECK [2020]015). All the participants must provide informed consent before they attend to the study. Consent for publication All the authors had read and agreed to the final version manuscript. The figures for this paper are approved for publication by individuals. Availability of data and materials Not applicable. We have no datasets included in this study protocol. In this research, volunteers will provide informed consent to ensure that blood indicators can be used in this study, and are not applicable to other channels. The result of this study will communicate with others via a peer-review journal. The full protocol can be accessed by contacting to us after the trial finish. Competing interests There is no a conflict of interest. Funding This study was supported by the Innovative Clinical Research Project of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (No. 2019IIT31) and Yang Wen Hui Guangdong Traditional Chinese Medicine Inheritance Studio (No. GDTCMO201905). The funding body approved our research design and will monitor our progress during the research, and review our research conclusions after the trial. Authors' contributions LZ carried out the conceptualization. DHX designed the study and drafted the manuscript. JH helped to design the study. MHL, CHH and JW will perform this study. MXZ will perform statistical analysis. TTY, WJZ, JJL, RNH and NX helped to revise the manuscript. Acknowledgements We would like to thank all the staff in this study. References Cross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, et al. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014;73(7):1323–30. Tang X, Wang S, Zhan S, Niu J, Tao K, Zhang Y, et al. The Prevalence of Symptomatic Knee Osteoarthritis in China: Results From the China Health and Retirement Longitudinal Study. Arthritis Rheumatol. 2016;68(3):648–53. Liu Q, Wang S, Lin J, Zhang Y. The burden for knee osteoarthritis among Chinese elderly: estimates from a nationally representative study. Osteoarthritis Cartilage. 2018;26(12):1636–42. Bruyère O, Honvo G, Veronese N, Arden NK, Branco J, Curtis EM, et al. 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Tables Table 1. the location of point set Point name Location The upper point of the medial collateral ligament A lateral tubercle located at the medial condyle of the femur The lower point of the medial collateral ligament the posterior part of the liriodendron area located at the medial condyle of the tibia The upper point of the lateral collateral ligament A lateral tubercle locating at the lateral condyle of the femur The lower point of the lateral collateral ligament The apex of the Capitula fibula The subpatellar ligament points The lower part of the patellar ligament The upper point of patella Directly above the patellar bottom and located in the deep surface of the quadriceps tendon The insertion of popliteal muscle Located behind the upper part of the medial tibia The medial popliteal fossa stimulation points Located at the medial wall of the popliteal triangle, between the semitendinosus and semimembranosus’ muscles. Table 2. Study schedules. T1-T3: from the first treatment period to the third treatment period. W7: one week after the whole treatment period; M3: the 3th month; M6: the 6th month STUDY SCHEDULE Period Screening Baseline Treatment End Follow-up Time W-1 W0 W1-W 6 W 7 M3 M6 Basic Eligibility √ Demography √ Physical examination √ Medical history √ Informed consent √ Outcomes WOMAC √ √ √ √ VAS √ √ √ √ X-ray examination √ √ Musculoskeletal ultrasound imaging √ √ plantar pressure measurement √ √ Maximum knee circumference √ √ Joint mobility √ √ Trial evaluation informed consent √ Adverse event √ √ Safety evaluation √ √ Supplementary Files SPIRITchecklist2013.doc Cite Share Download PDF Status: Published Journal Publication published 20 Apr, 2021 Read the published version in Trials → Version 1 posted Editorial decision: Major revision 05 Feb, 2021 Review # 1 received at journal 24 Jan, 2021 Review # 2 received at journal 24 Jan, 2021 Review # 4 received at journal 23 Jan, 2021 Review # 3 received at journal 23 Jan, 2021 Reviewer # 4 agreed at journal 22 Jan, 2021 Reviewer # 3 agreed at journal 21 Jan, 2021 Reviewer # 2 agreed at journal 18 Jan, 2021 Reviewers invited by journal 18 Jan, 2021 Reviewer # 1 agreed at journal 18 Jan, 2021 Editor assigned by journal 11 Sep, 2020 Submission checks completed at journal 27 Aug, 2020 First submitted to journal 11 Jul, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-35085","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":1775796,"identity":"be373fec-12a6-4671-b60f-138def475a90","order_by":0,"name":"Danghan Xu","email":"","orcid":"","institution":"the first affiliated hospital of guangzhou university of chinese medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Danghan","middleName":"","lastName":"Xu","suffix":""},{"id":1775797,"identity":"748b6f5a-2358-4b5d-861b-14a854f98f46","order_by":1,"name":"Minghui 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Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Liang","middleName":"","lastName":"Zheng","suffix":""}],"badges":[],"createdAt":"2020-06-12 04:35:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-35085/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-35085/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-021-05247-z","type":"published","date":"2021-04-20T21:07:25+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":2131110,"identity":"541f3a9c-8c88-4482-8fd9-209c379a5202","added_by":"auto","created_at":"2020-08-28 15:22:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":18476,"visible":true,"origin":"","legend":"Flowchart of the study design. ","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-35085/v1/floatimage1.png"},{"id":2131111,"identity":"a73bc472-b4dc-4ecf-bea9-8b82246be150","added_by":"auto","created_at":"2020-08-28 15:22:27","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":243566,"visible":true,"origin":"","legend":"the needle-knife","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-35085/v1/floatimage2.jpeg"},{"id":13587878,"identity":"26e9133c-1ed8-4821-a9c7-6b6ef21b5d5f","added_by":"auto","created_at":"2021-09-17 04:52:53","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":419849,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-35085/v1/24862c83-c19e-411c-ae4a-e5b0e2fa5340.pdf"},{"id":2131113,"identity":"dfa4b4a6-5199-45ab-9b23-5fc9d28af40c","added_by":"auto","created_at":"2020-08-28 15:22:28","extension":"doc","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":129536,"visible":true,"origin":"","legend":"","description":"","filename":"SPIRITchecklist2013.doc","url":"https://assets-eu.researchsquare.com/files/rs-35085/v1/SPIRITchecklist2013.doc"}],"financialInterests":"","formattedTitle":"Effect of Acupotomy in Knee Osteoarthritis Patients: Study Protocol for A Randomized Controlled Trial","fulltext":[{"header":"Background","content":" \u003cp\u003eAs the 11th highest contributor to global disability, knee osteoarthritis (KOA) triggers burdensome pressure for society and family \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. In China, symptomatic knee osteoarthritis patients are common \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Symptomatic knee osteoarthritis will cause pain and impaired knee function. 3.9% of knee osteoarthritis patients are suffering from these severe torments, which leads them to disability easily \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e. The pharmacologic therapy is not recommended because of its limited efficacy and safety issues \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Non-pharmacologic therapy has been used a lot in treating knee osteoarthritis \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. For instence, Lifestyle adjustments, weight loss, and proper exercise are the first line recommended methods \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. However, patients with these treatments usually have poorer adherence \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. Thus, we are seeking for an effective non-drug therapy with better adherence to treat knee osteoarthritis.\u003c/p\u003e \u003cp\u003eAcupotomy therapy is a special technique of acutherapy. Unlike standard acupuncture needles, acupotomy therapy will use a needle-knife with a thicker diameter and flat needle. This needle-knife can enter deep tissues to loosen adhesion. Acupotomy therapy has been used to treat knee osteoarthritis for many years, because of its longer treatment session and satisfying effect in clinical practice. Although previous studies \u003csup\u003e[\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e have showed the efficacy of acupotomy therapy, there is no high-quality clinical research in this field. The sloppy designs of past studies are detrimental to the power of their conclusion.\u003c/p\u003e \u003cp\u003eTherefore, we design a randomized, single blinding, sham controlled trials to explore the efficacy of acupotomy therapy in treating knee osteoarthritis patients.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on the Declaration of Helsinki, we will design a parallel, block randomization, single-blinding, sham controlled trials. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 1). This study will be performed in the First Affiliated Hospital of Guangzhou University of Chinese Medicine from June 2020 to June 2023 (Figure 1). We will recruit volunteers via advertising, posters and contacting community doctors, and enroll those who meet inclusion criteria.\u003c/p\u003e\n\u003cp\u003eFig. 1 Flowchart of the study design.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(1) Patients meeting the I, II, and III levels of Kellgren-Lawrecne's radiological diagnostic criteria \u003csup\u003e[11]\u003c/sup\u003e;\u003c/p\u003e\n\u003cp\u003e(2) The score of pain visual analog scale is above 4 points in the past month;\u003c/p\u003e\n\u003cp\u003e(3) Age is between 40-70 years old;\u003c/p\u003e\n\u003cp\u003e(4) Those who have not taken other related treatment drugs or adopted related treatment methods within 2 weeks;\u003c/p\u003e\n\u003cp\u003e(5) Participate should provide informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion Criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(1) Pregnant or lactating women, or women with a pregnancy plan during the trial;\u003c/p\u003e\n\u003cp\u003e(2) Patients with infectious diseases or serious diseases, such as cardiovascular, cerebrovascular, liver, kidney, hematopoietic system;\u003c/p\u003e\n\u003cp\u003e(3) Patients with local infection, ulceration, vascular nerve damage or deep abscess in the knee joint;\u003c/p\u003e\n\u003cp\u003e(4) Patients with a history of severe knee trauma, or who have undergone surgery or arthroscopy;\u003c/p\u003e\n\u003cp\u003e(5) Patients with other diseases that cause knee pain, such as tumors, knee joint tuberculosis, rheumatoid arthritis, gouty arthritis, etc.;\u003c/p\u003e\n\u003cp\u003e(6) Patients who have taken oral corticosteroids or received intra-articular knee injection treatment within 1 month; or have participated in other clinical trials within 3 months;\u003c/p\u003e\n\u003cp\u003e(7) People who are allergic to the medical devices involved in this trial; contraindications to the use of indomethacin plaster, such as those with a history of allergy to indomethacin, those with liver and kidney dysfunction (alanine aminotransferase (ALT), aspart The amino acid transaminase (AST) is more than 2 times the normal value, and the blood creatinine (cr) is more than the normal value). Patients who have induced asthma, urticaria or allergic reactions after taking aspirin or other non-steroidal anti-inflammatory drugs may have nonsteroidal Patients with a history of gastrointestinal bleeding or perforation after anti-inflammatory drugs, patients with active gastrointestinal ulcer bleeding, or patients with previous recurrent ulcers / bleeds, patients with severe heart failure, perioperative coronary artery bypass surgery, etc. ;\u003c/p\u003e\n\u003cp\u003e(8) Patients with bleeding tendency, such as long-term use of warfarin, aspirin and other anticoagulants;\u003c/p\u003e\n\u003cp\u003e(9) People with an abuse history of sedative hypnotics, opioid analgesics, and alcohol;\u003c/p\u003e\n\u003cp\u003e(10) Patients who cannot cooperate with relevant experiments and measurements.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAcupotomy group\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe patients are in a supine position with the knee flexed 30 ~ 45 \u0026deg;. A cushion is placed below the knee. The physicians will select 6 points from a point set as follow. The point set contains 8 points, including the upper point and lower point medial collateral ligament of the affected knee joint, the upper point and lower point lateral collateral ligament, the subpatellar ligament points, the upper point of the patella, the muscle insertion of the popliteal muscle, and the medial popliteal fossa stimulation points. We will stimulate 6 points for unilateral knee pain and 12 points for bilateral knee pain (Table 1).\u003c/p\u003e\n\u003cp\u003eAfter standard disinfection, the physicians will operate Hanzhang Ⅰ type No.4 straight needle knife (Beijing Huaxia Needle Knife Medical Equipment Factory) to run acupotomy therapy (Figure 2). All these physicians have more than 5 years of acupotomy experience and will be retrained 16 hours before the study begins.\u003c/p\u003e\n\u003cp\u003eThe incision line is consistent with the longitudinal axis of the lower limb. The body of needle-knife is perpendicular to the skin. The doctor operates according to the procedures of fixed point, orientation, pressure and penetration. When the needle knife reaches the target depth, the doctors perform a manual operation. After the operation, the needle-knife is pulled out, and local hemostasis is applied for 3 minutes. The wound was disinfected with iodine and the needle eye was covered with a band-aid. Patients receive acupotomy therapy 2 sessions for 2 weeks（once a week）.\u003c/p\u003e\n\u003cp\u003eTable 1. the location of point set\u003c/p\u003e\n\u003cp\u003eFig 2. the needle-knife\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSham acupotomy group\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePatients assigned to sham acupotomy group will receive the mock acupotomy, which will be performed just like real acupotomy, but without manual stimulation to achieve any real effect. The needle-knife will pierce through the skin only and stay under the skin for 10 seconds to simulate manipulation time. Patients will receive 2 sessions of sham acupotomy for 2 weeks（once a week）.\u003c/p\u003e\n\u003cp\u003eAll the patients of two groups are allowed to use drugs. Clinicians will give patients indomethacin cream (manufacturer: Nipro Pharma Corporation Saitama Site Plant 2, import drug registration number H20181060) for external use, once daily after 24 hours of acupotomy. They will receive indomethacin cream 12 times in total.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome Measurement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe had selected both clinical outcomes and surrogate outcomes to assess the efficacy of acupotomy. All the outcomes will be measured at baseline and one week after the end of treatment. Besides, we will follow up for WOMAC index and VAS in the 3\u003csup\u003erd\u003c/sup\u003e month and 6\u003csup\u003eth\u003c/sup\u003e month after the end of treatment (Table 2). Before the study begins, we will train the related investigators.\u003c/p\u003e\n\u003cp\u003eTable 2. Study schedules. T1-T3: from the first treatment period to the third treatment period. W7:\u003c/p\u003e\n\u003cp\u003eone week after the whole treatment period; M3: the 3th month; M6: the 6th month\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePrimary Outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWestern Ontario and McMaster Universities Osteoarthritis Index (WOMAC)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe WOMAC index is always used to assess knee osteoarthritis symptoms \u003csup\u003e[12]\u003c/sup\u003e. The scale includes 24 items in three parts, including 5 pain items, 2 stiff items, and 17 joint function items. The scoring record uses a 10cm long visual analog scale scoring rule. The two ends are 0-point and 10-point. 0 points indicate that the item is asymptomatic, and 10 points indicates the most serious degree of the item.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary Outcome\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eVisual Analog Scale (VAS)\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eVAS scale is a commonly used scale to reflect the degree of body pain \u003csup\u003e[13]\u003c/sup\u003e. A 10 cm length VAS scale will be used. The two ends are 0-point and 10-point respectively. The 0 presents painless and 10 shows the most severe pain which is intolerable.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePlantar Pressure Distribution Tests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003ePlantar pressure distribution tests can observe the function of patients' knee joints \u003csup\u003e[14]\u003c/sup\u003e. This test uses the Plantar Pressure Distribution Test System (Belgium RSscan Footsacn1.0m). A rehabilitation technician will in charge of measurement. We will collect balanceparameters (foot angle and subtalar joint mobility) to assess the stability of knee joint medial and lateral. The bigger balance parameters indicate the worse stability. Besides, impulse parameters, known as the ratio of the heel and forefoot, will be used to analyze knee buffering stability. The larger the ratio, the stronger the stability.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eX-ray examination\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eInterrogation of the results of the patient's front and lateral knee X-rays was performed by an imaging physician. This measurement aims to monitor whether there are existences of osteophyte formation, joint space narrowing, subchondral sclerosis, cartilage degeneration, osteoporosis, valgus deformity, and varus deformity.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMusculoskeletal Ultrasound\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eUltrasonography has also been proven as a useful tool in monitoring knee osteoarthritis treatment effectiveness \u003csup\u003e[15]\u003c/sup\u003e. Specialized ultrasound doctors will collect data via Philip HP SONOS 5500 ultrasound imaging machine. We will pay attention to the knee joint fluid volume and synovial film thickness. These data will show us the degree of damage and repair of knee.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMaximum Knee Circumference\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThis indicator is used to assess the soft tissue lesions around the knee joint \u003csup\u003e[16]\u003c/sup\u003e. When conducting the assessment, the patients will be asked to lie supine with the knee joint straight. The doctor will use a soft ruler to measure the circumference of the knee joint along the upper and lower pole of the patella, of the metatarsal bone, and measure around the knee joint.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eJoint Mobility\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eJoint mobility is also used to check knee function \u003csup\u003e[17]\u003c/sup\u003e. The arthrometer will be used to measure knee mobility. The patient being tested is positioned on his/her side with the affected leg being measured facing upwards. First, the lateral femoral condyle is positioned over the center of rotation of the arthrometer. Then position the fixed arm along the middle of the femoral joint, and fix the movable arm along the fibula. Lastly, let the patient extend the knee joint as much as possible, and then bend the knee as much as possible, and measure the flexion and extension motion range by moving the movable arm.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample Size\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eReferring to a previous study \u003csup\u003e[18]\u003c/sup\u003e, we determined that the change in the WOMAC index before and after treatment in the acupotomy group was 16.34 \u0026plusmn; 4.19. Then the change in the WOMAC index before and after treatment in the sham acupotomy group was 14.2 \u0026plusmn; 4.19, and the effect size was 2.14 \u003csup\u003e[19]\u003c/sup\u003e. The sample sizes should provide 80% of statistical power and significance level of 0.05.\u003c/p\u003e\n\u003cp\u003eWe calculated the sample sizes of 124 with repeated measurement design via the SAS software package (version 9.4, Tokyo, Japan). Considering the 10% loss of patients during the research, we had decided to enroll 136 participants finally.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA biostatistician will generate a block random number list at a ratio of 1: 1via Stata 14.0 software package. The block size is not discovered until study finishing because of allocation concealment. An independent staff, who does not take part in the performance period of this study, will seal the random number by the opaque envelopes. Then the primary investigator will save these envelopes and open one of them when a participant is enrolled.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBlinding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study takes a single-blind approach. The operators will mock the procedure of standard acupotomy therapy in the sham acupotomy group. The operators pierce through the skin only and do not stimulate the relevant ligaments and muscles. The needle-knife will stay under the skin for 10 seconds without any manipulation. At the same time, this experiment will blind other folks (data administrators, biostatisticians, programmers, measurement evaluators, etc.) to minimize performance bias.\u003c/p\u003e\n\u003cp\u003eFor the sake of protecting the rights of the subjects, we will approve free acupotomy treatment for the sham acupotomy group at the end of the trial.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDate Management and Monitor\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe will train all the staff to ensure data quality. The researchers will fill the data in the Case Report Forms (CRF) and sign it. CRF does not allow alteration directly. The researchers must report to the primary investigator if they need to alter the CRF. Any changes in CRF need to be signed and dated. Data administrators will enter data into the computer. The CRF and the computer will be locked in the research center, while the primary investigator keeps the key only. The original data will be kept in the research center rather than publish. The data can be access through research center if someone applies with reasons.\u003c/p\u003e\n\u003cp\u003eThe data monitoring and management committee is composed of the Scientific Research Department of the First Affiliated Hospital of Guangzhou University of Chinese Medicine. They independently review and monitor research data. The South China Acupuncture Research Center Clinical Sub-center will form a quality monitoring committee. These committees will visit our clinical research center every 6 months to review and monitor the trial. The study group will run a conference to review this trial every month.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSafety Monitor\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAcupotomy therapy may trigger adverse events including dizziness and local hematoma. When dizziness occurs during treatment, the doctor should stop the treatment immediately. Then the doctor will lay down on the pillow, and take warm water to take the service. If hematoma remains after treatment, the patient will apply a local cold compress, and switch to a hot compress at 24 hours to promote the dissipation and absorption of blood stasis. If an adverse drug reaction occurs, the drug should be discontinued. Active clinical observation and symptomatic treatment should be carried out.\u003c/p\u003e\n\u003cp\u003eEthics Committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine will monitor the safety of this trial and furnish us with advices (e.g., endpoint adjustment) if it is necessary. When an adverse event occurs in a patient, the researchers should record the detail, such as time, severity, duration, treatment measures, and event outcomes. The responsible doctor will determine the causal relationship between the treatment method and the adverse event, and decide to continue or terminate the study. Relevant information must be reported to the ethics committee on the same day.\u003c/p\u003e\n\u003cp\u003eThe following are the criteria for terminating the study: (1) the subject has a serious adverse event or the subject has requested to suspend participation in the trial, or the trial operator believes that it is necessary for the subject to suspend the trial;(2) during the study, the subject is found to have a systemic disease that could not be detected before the start of the clinical trial;(3) for other reasons, researchers believe that patients are not suitable for continued treatment;(4) patients receive privately other interventions that may affect outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistics Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePer-protocol subjects\u0026rsquo; analysis and intention-to-treat analysis were used to analyze the efficacy. The safety analysis set is used to analyze the safety evaluation.\u003c/p\u003e\n\u003cp\u003eWe will develop a statistical analysis plan with a statistician. The statistician R 3.4.3 software package is used to performs descriptive statistics, exploratory analysis and dropout analysis. The result is statistically significant when the P-value is less than 0.05. In the intention-to-treat analysis, when the data is missing, the last observation is used for interpolation. Then we will select sensitive analysis for the result.\u003c/p\u003e\n\u003cp\u003eFor continuous variables that obey normal distribution and meet homogeneity of variance, we will use Student\u0026rsquo;s t-test. if continuous variables cannot meet the condition mentioned above, the Mann-Whitney test or Wilcoxon test will be used. A chi-square test will be performed for discrete or categorical variables. When analyzing data from repeated measurements, we will use analysis of variance or analysis of covariance.\u003c/p\u003e\n\u003cp\u003eFor safety analysis, we will use descriptive analysis at first. Subsequently, the incidence of adverse reactions between the two groups will be compared. The causality for the severity of adverse reactions and the needle-knife operation should be considered in the comparison. If there are a large number of adverse reactions, the relationship with the intervention time and baseline characteristics should be analyzed.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eKnee osteoarthritis is a chronic disease with pain, swelling, stiffness, restricted movement, popping or deformity \u003csup\u003e[20]\u003c/sup\u003e. It is associated with gender, age, body weight, physical activity, occupation and biochemical factors etc\u003csup\u003e[21]\u003c/sup\u003e. There are three views of knee osteoarthritis pathological mechanism \u003csup\u003e[22]\u003c/sup\u003e. First of all, mechanical loading causes changes in biological stress, which can damage knee cartilage. Furthermore, synovial inflammation induces cartilage to secrete too much matrix metalloproteinase, which can damage knee cartilage. In addition, some adipokines, such as leptin and adipsin, are known as one of the pathological mechanisms in triggering cartilage impaired.\u003c/p\u003e\n\u003cp\u003eDifferent guidelines had provided different suggestions of clinical practice in knee osteoarthritis\u003csup\u003e [23]\u003c/sup\u003e. The physicians always use paracetamol (acetaminophen) and NSAIDs (celecoxib, indomethacin, etc. ) to deal with knee osteoarthritis problems according to the guidelines \u003csup\u003e[4, 24-26]\u003c/sup\u003e. But patients cannot use these drugs for long time. Paracetamol (acetaminophen) does a little work for patients\u0026rsquo; pain and stiffness and physical function\u003csup\u003e [27]\u003c/sup\u003e. Besides, paracetamol (acetaminophen) brings hepatotoxicity\u003csup\u003e [28]\u003c/sup\u003e and induces adverse reactions in kidney, cardiovascular and gastrointestinal tract with a long-term use \u003csup\u003e[29]\u003c/sup\u003e. NSAIDs will increase the risks of adverse cardiovascular outcomes \u003csup\u003e[30]\u003c/sup\u003e and upper gastrointestinal complications \u003csup\u003e[31]\u003c/sup\u003e. Hence, non- pharmacologic therapies play an essential role in knee osteoarthritis treatment\u003csup\u003e [32]\u003c/sup\u003e. Traditional Chinese Medicine can also make a contribution in this field, such as acupuncture\u003csup\u003e [33]\u003c/sup\u003e, moxibustion \u003csup\u003e[34]\u003c/sup\u003e, Taiichi and massage \u003csup\u003e[35]\u003c/sup\u003e. Compared with other non-drug therapies, acupotomy therapy is a better choice for the treatment of knee osteoarthritis. It is less frequent, which is good for persistence. Besides, acupotomy not only can relief pain but also improve patients\u0026rsquo; joint mobility.\u003c/p\u003e\n\u003cp\u003eAs a special type of acutherapy, acupotomy therapy can improve knee osteoarthritis symptoms via different pathways. Knee biomechanical will be restored by acupotomy due to its function of biological street adjustment \u003csup\u003e[36]\u003c/sup\u003e. Acupotomy can also curb inflammation \u003csup\u003e[37-38]\u003c/sup\u003e. The reduction of IL-1\u0026beta;, IL-6, and TNF-\u0026alpha; suppress the expression of MMP-1, MMP-3, and MMP-13, which is conducive to knee cartilage. In a word, acupotomy therapy promotes chondrocyte repair and regulate cartilage metabolism \u003csup\u003e[39]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe clinical research confirmed acupotomy effect of knee osteoarthritis \u003csup\u003e[9-10]\u003c/sup\u003e. However, the study designs of the trials are both inadequate. They both selected acupuncture as a comparison, which fail to demonstrate acupotomy efficacy powerfully. One used inappropriate randomization procedures and didn\u0026rsquo;t use blinding. While another had a small sample size and used scale as outcome only. Thus, we had designed a stricter study to explore the efficacy and safety of acupotomy in knee osteoarthritis. We had selected sham acupotomy as a comparison. Besides, as we know, this program is the first single-blinding design in acupotomy research. Moreover, we will use clinical outcomes (the WOMAC index, the visual analog scale, and joint mobility) and surrogate outcomes (musculoskeletal ultrasound, X-ray examination, plantar pressure distribution test, maximum knee circumference) at the same time.\u003c/p\u003e\n\u003cp\u003eThis study has some limitation. Firstly, we will enroll the early and mid-term patients only, thus we cannot observe the effect of acupotomy in the late-period patients. Secondly, the long-term effect cannot be monitored owing to 6 months follow-up. Lastly, this study will be performed in China so the conclusion may not suitable for other races.\u003c/p\u003e\n\u003cp\u003eTo summary, we will perform a parallel, block randomized, single-blinding, sham acupotomy controlled trial to scrutinize the efficacy and safety of acupotomy in knee osteoarthritis patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eKOA, Knee Osteoarthritis\u003c/p\u003e\n\u003cp\u003eWOMAC, Western Ontario and McMaster Universities Osteoarthritis Index\u003c/p\u003e\n\u003cp\u003eVAS, Visual Analog Scale\u003c/p\u003e\n\u003cp\u003eCRF, Case Report Form\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study had be performed since June 2020. The study protocol is vision 3.0 (2020.4.27). We are recruiting participants from June 1, 2020, to June 30, 2022.\u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e \u003cp\u003eThis trial had been approved by the ethical committee of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (No. ZYYECK [2020]015). All the participants must provide informed consent before they attend to the study.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent for publication\u003c/strong\u003e \u003cp\u003eAll the authors had read and agreed to the final version manuscript. The figures for this paper are approved for publication by individuals.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e \u003cp\u003eNot applicable. We have no datasets included in this study protocol. In this research, volunteers will provide informed consent to ensure that blood indicators can be used in this study, and are not applicable to other channels. The result of this study will communicate with others via a peer-review journal. The full protocol can be accessed by contacting to us after the trial finish.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eCompeting interests\u003c/strong\u003e \u003cp\u003eThere is no a conflict of interest.\u003c/p\u003e \u003c/p\u003e \u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis study was supported by the Innovative Clinical Research Project of the First Affiliated Hospital of Guangzhou University of Chinese Medicine (No. 2019IIT31) and Yang Wen Hui Guangdong Traditional Chinese Medicine Inheritance Studio (No. GDTCMO201905). The funding body approved our research design and will monitor our progress during the research, and review our research conclusions after the trial.\u003c/p\u003e \u003ch2\u003eAuthors' contributions\u003c/h2\u003e \u003cp\u003eLZ carried out the conceptualization. DHX designed the study and drafted the manuscript. JH helped to design the study. MHL, CHH and JW will perform this study. MXZ will perform statistical analysis. TTY, WJZ, JJL, RNH and NX helped to revise the manuscript.\u003c/p\u003e \u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eWe would like to thank all the staff in this study.\u003c/p\u003e "},{"header":"References","content":"\u003col\u003e\u003cli\u003e \u003cspan\u003eCross M, Smith E, Hoy D, Nolte S, Ackerman I, Fransen M, et al. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. 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Knee osteoarthritis pain in the elderly can be reduced by massage therapy, yoga and tai chi: A review. Complement Ther Clin Pract. 2016;22:87\u0026ndash;92.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eWang L-J, Shi X-W, Zhang W, Wang T, Zhou S, Guo C-Q. Effect of needle knife intervention on tensile mechanics of femoral quadriceps tendon in rabbits with knee osteoarthritis. Zhongguo Gu Shang. 2019;32(5):462\u0026ndash;8.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eJie Y, Shunpei M, Xiufen Z. The Effect of Acupotomy on IL-1β, IL-6 and TNF-α in the Synovial Fluid of Rabbit OA. Chinese Journal of Traditional Medical Traumatology \u0026amp; Orthopedics. 2002(4):3.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eHuang Y, Jin Y, Li N, Lei L, Yu F, Li Y, etc. Acupuncture, electroacupuncture and Yuanli targeting MMP-1, MMP-3, MMP-13 and TIMP- The influence of 1 expression [J]. Chinese Journal of Traditional Chinese Medicine, 2014,29 (08): 2600-2604.6.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eMa S-N, Xie Z-G, Guo Y, Yu J-N, Lu J, Zhang W, et al. Effect of Acupotomy on FAK-PI3K Signaling Pathways in KOA Rabbit Articular Cartilages. Evid Based Complement Alternat Med. 2017:4535326.\u003c/span\u003e \u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. the location of point set\u003c/p\u003e\n\u003ctable border=\"1\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"325\"\u003e\n\u003cp\u003e\u003cstrong\u003ePoint name\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"379\"\u003e\n\u003cp\u003e\u003cstrong\u003eLocation\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"325\"\u003e\n\u003cp\u003eThe upper point of the medial collateral ligament\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"379\"\u003e\n\u003cp\u003eA lateral tubercle located at the medial condyle of the femur\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 48px;\"\u003e\n\u003ctd style=\"height: 48px;\" width=\"325\"\u003e\n\u003cp\u003eThe lower point of the medial collateral ligament\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 48px;\" width=\"379\"\u003e\n\u003cp\u003ethe posterior part of the liriodendron area located at the medial condyle of the tibia\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"325\"\u003e\n\u003cp\u003eThe upper point of the lateral collateral ligament\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"379\"\u003e\n\u003cp\u003eA lateral tubercle locating at the lateral condyle of the femur\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"325\"\u003e\n\u003cp\u003eThe lower point of the lateral collateral ligament\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"379\"\u003e\n\u003cp\u003eThe apex of the Capitula fibula\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"325\"\u003e\n\u003cp\u003eThe subpatellar ligament points\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"379\"\u003e\n\u003cp\u003eThe lower part of the patellar ligament\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 48px;\"\u003e\n\u003ctd style=\"height: 48px;\" width=\"325\"\u003e\n\u003cp\u003eThe upper point of patella\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 48px;\" width=\"379\"\u003e\n\u003cp\u003eDirectly above the patellar bottom and located in the deep surface of the quadriceps tendon\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 35px;\"\u003e\n\u003ctd style=\"height: 35px;\" width=\"325\"\u003e\n\u003cp\u003eThe insertion of popliteal muscle\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 35px;\" width=\"379\"\u003e\n\u003cp\u003eLocated behind the upper part of the medial tibia\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 48px;\"\u003e\n\u003ctd style=\"height: 48px;\" width=\"325\"\u003e\n\u003cp\u003eThe medial popliteal fossa stimulation points\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"height: 48px;\" width=\"379\"\u003e\n\u003cp\u003eLocated at the medial wall of the popliteal triangle, between the semitendinosus and semimembranosus\u0026rsquo; muscles.\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Study schedules. T1-T3: from the first treatment period to the third treatment period. W7: one week after the whole treatment period; M3: the 3th month; M6: the 6th month\u003c/p\u003e\n\u003ctable border=\"1\" width=\"707\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\" width=\"707\"\u003e\n\u003cp\u003e\u003cstrong\u003eSTUDY SCHEDULE\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003e\u003cstrong\u003ePeriod\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u003cstrong\u003eScreening\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u003cstrong\u003eBaseline\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u003cstrong\u003eEnd \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"2\" width=\"124\"\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003e\u003cstrong\u003eTime \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u003cstrong\u003eW-1\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u003cstrong\u003eW0\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u003cstrong\u003eW1-W\u003c/strong\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u003cstrong\u003eW\u003c/strong\u003e\u003cstrong\u003e7\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u003cstrong\u003eM3\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u003cstrong\u003eM6\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\" width=\"707\"\u003e\n\u003cp\u003e\u003cstrong\u003eBasic \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003eEligibility\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003eDemography\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003ePhysical examination\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003eMedical history\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003eInformed consent\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\" width=\"707\"\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes \u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003eWOMAC\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003eVAS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003eX-ray examination\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003eMusculoskeletal ultrasound imaging\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003eplantar pressure measurement\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003eMaximum knee circumference\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003eJoint mobility\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"7\" width=\"707\"\u003e\n\u003cp\u003e\u003cstrong\u003eTrial evaluation\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003einformed consent\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003eAdverse event\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"268\"\u003e\n\u003cp\u003eSafety evaluation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"83\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"81\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"85\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"67\"\u003e\n\u003cp\u003e\u0026radic;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"62\"\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e "}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"acupotomy, needle-knife, knee osteoarthritis, study protocol, randomized controlled trial","lastPublishedDoi":"10.21203/rs.3.rs-35085/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-35085/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u003c/p\u003e\u003cp\u003eSymptomatic knee osteoarthritis patients are common in China. Pharmacologic therapy is not the first recommendation because of its safety issues. Non-pharmacologic therapy, such as lifestyle adjustments, weight loss, and proper exercise is strongly recommended to use in knee osteoarthritis. But the adherance rate is very poor. Acupotomy therapy, as an effective treatment for knee osteoarthritis, is lack of high quality randomized controlled trials. This study set out to investigate the efficacy of acupotomy in patients with knee osteoarthritis.\u003c/p\u003e\u003cp\u003eMethods\u003c/p\u003e\u003cp\u003e136 patients will be enrolled in the First Affiliated Hospital of Guangzhou University of Chinese Medicine, and assigned into acupotomy group or sham acupotomy group according to the block randomization number. The acupotomy group will receive 2 sessions of acupotomy for 2 weeks(once a week). The sham group will receive 2 sessions of sham stimulation for 2 weeks༈once 2 week. All the patients will use indomethacin cream externally. The primary outcome is the WOMAC index and the secondary outcomes are VAS, plantar pressure distribution test, X-ray examination, musculoskeletal ultrasound, maximum knee circumference, and joint mobility. We will measure them at baseline, one week after the end of treatments, the third month and sixth month follow up.\u003c/p\u003e\u003cp\u003eDiscussion\u003c/p\u003e\u003cp\u003eAs we know, this is the first single-blinding and sham controlled design in acupotomy research. We aim to prove the efficacy of acupotomy in treating knee osteoarthritis.\u003c/p\u003e\u003cp\u003eTrial registration\u003c/p\u003e\u003cp\u003eChinese Clinical Trial Registry: ChiCTR2000033047(2020-5-18).\u003c/p\u003e","manuscriptTitle":"Effect of Acupotomy in Knee Osteoarthritis Patients: Study Protocol for A Randomized Controlled Trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-08-28 15:22:26","doi":"10.21203/rs.3.rs-35085/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2021-02-06T00:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2021-01-25T00:00:00+00:00","index":1,"fulltext":"Recommendation: Minor Revision\nForm responses:\n---\n\nComments to Author:\n---\nThis is an interesting treatment, not quite acupuncture, not quite minor surgery.\n\nGrammatical Issues:\n\nPg 1, Line 33: insert comma after \"exercise\"\n Line 36-37: revise sentence. \"Is it currently unclear if acupotomy therapy is an effective treatment for knee osteoarthritis due to a lack of high quality…\"\n\nPg 2, Ln 12: \"As far as we know…\"\nPg 3, Ln 1: strike \"for\"\n Ln 12: \"adhesions\"\n Ln 15: how many years?\n Ln 17: does not follow from previous clause\n Ln 28: \"we designed\"\nPg 4, Ln 28: error in sentence\n Ln 36-39: error in sentence\nPg 5, Ln 18: \"as follows\"\nPg 7,Ln 8: \"was\" …keep tense consistent in paragraph\nPg 9, Ln 26: insert space b/w balance parameters\n Ln 45: \"was\" …keep tense consistent throughout\nPg 13, Ln 17: this makes it sound like the doctor lays down on the pillow…\nPg 14 Ln 20: tense is inconsistent\nPg 16 Ln 12: change persistence to \"compliance\"\n Ln 15: change to \"relieve\" pain\n Ln 20: change to \"biomechanics\"\n Ln 23: I am unclear what the meaning of \"biological street adjustment\" is\n\nLimitations: Single blinded, relatively short-term follow-up for a chronic arthritis condition.\n\nCan sham acupotomy even without the needle-knife manipulation still create some \"acupuncture\"-like benefits due to its invasive nature of stimulating the immune system?\n\nWill the use of indomethacin (NSAID) cream cloud the results? Why include that? Is it a normal part of acupotomy treatment?\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Level of interest: **An article of limited interest**\n* Quality of written English: **Needs some language corrections before being published**\n* Quality of figures: **- Acceptable**\n* Statistical review: **- Yes, but I do not feel adequately qualified to assess the statistics**\n* Declaration of competing interests: **I declare that I have no competing interests.**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: **\nI agree to the open peer review policy of the journal**\n* Were you mentored through this peer review?: **No**\n"},{"type":"editorInvitedReview","content":"","date":"2021-01-25T00:00:00+00:00","index":2,"fulltext":"Recommendation: Minor Revision\nForm responses:\n---\n\nComments to Author:\n---\nMajor points:\n\nThe authors submit a manuscript with logical arguments and clinical relevance.\n\nAbstract\nLine 55: Can the authors clarify if the sham group will receive treatment once a week or not. The line reads, \"once 2 week\".\nLine 6 - 9: Can the authors rephrase \"we will measure them\" to measurements will be taken at baseline\nLine 12: Can the authors rephrase \"single-blinding\" with \"single-blind\". Also, can the authors state if the outcome assessors for secondary outcomes will be blinded?\n\nIntroduction\nLine 57 - 4: Can the authors update the argument on non-pharmacological interventions with data on the effectiveness and adherence rates. I am not sure what proper exercise means in this context. Can the author consider using a scientific term or provide further explanation.\nLine 6-26: Can the authors expand on what aspects of this therapy is efficacious and in what settings? The justification for this study needs further clarity or needs to be expanded. If previous studies have not shown conclusive evidence, what designs were used, and what aspects of quality underpins uncertainty. Please, explain what the previous studies are unreliable, e.g. high risk of bias, adequate reporting of side/adverse events, or sample size and how this impact findings.\n\n\nMethodology\n\nThe authors provide a clear rationale of the burden of the disease, clinical symptoms, and management strategies for patients.\n\nStudy design\nLine 50: Please, provide the reference for the SPIRIT guidelines.\nLine 50: Please, provide details of the retaining programme designed for physicians and recruitment strategy.\n\nInclusion criteria:\nThe inclusion criteria excludes many patients in the intended age group seen in clinical practice and may affect its generalisability. Can the authors please, discuss the implications in the discussion?\n\nIntervention\nLine 1: Can the authors provide more details/be more explicit about the \"manual operation\". \nLine 46: please change \"all physicians have more than 5 years experience\" to \"physicians selected will have more than 5 years experience\".\nLine 51: If applicable, how will adherence to the co-intervention - indomethacin be assessed/addressed.\nLine 7: Can the authors consider rephrasing the sentence to present tense?\nLine 45-49: Can the authors consider rephrasing the sentence to present tense? This approach which was common across the manuscript, made the protocol confusing to read at times.\nLine 12-31: Please, revise the entire sentence on safety monitoring, it is unclear, especially, lines Line 17-20: Furthermore, more details on the consent process might be helpful.\nLine 34-37: Can the authors provide further details on the limitations of using last observation carried forward to interpret findings in the discussion.\n\nSecondary outcomes not outcome?\nLine 25: can the authors change -The statistician R- to \"The statistical package R\"\nLine 39: can the authors change -that obey- to \"That follow or meet assumptions of a\"\nLine 1-4: Can the authors provide further details on the planned approach for analysing differences in adverse reactions?\n\nMinor points:\n\nDiscussion\n\nCan the authors edit line 14-17? How is knee OA associated with these factors? Please, expand.\n\nLine 14-20: Please, provide references for the different guidelines or edit the sentence to a singular guideline.\n\nLine 6-12: Can the authors edit the sentence comparing acupotomy therapy to other treatments, e.g. acupuncture [33], moxibustion [34], Taiichi and massage to reflect uncertainty rather than definitive evidence.\n\nLine 36: can the authors replace confirmed with evaluated.\n\nLine 47: can the authors please edit this sentence; it is not clear or incomplete when discussing the scale used by the authors. Also, please, provide references for these studies. \n\nLine 6 - 13: can the authors explain what they mean by early and mid-term patients, vs late-period patients.\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Level of interest: **An article whose findings are important to those with closely related research interests**\n* Quality of written English: **Not suitable for publication unless extensively edited**\n* Quality of figures: **- Acceptable**\n* Statistical review: **- Yes, but I do not feel adequately qualified to assess the statistics**\n* Declaration of competing interests: **None**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: **\nI agree to the open peer review policy of the journal**\n* Were you mentored through this peer review?: **No**\n"},{"type":"editorInvitedReview","content":"","date":"2021-01-24T00:00:00+00:00","index":4,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"editorInvitedReview","content":"","date":"2021-01-24T00:00:00+00:00","index":3,"fulltext":"Recommendation: Major Revision\nForm responses:\n---\n\nComments to Author:\n---\n1.Quality of written English needs to be improved.\n2.There is no diagnostic criteria.\n3.It is better to add the quality of life into the Outcome Measurement.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Level of interest: **An article whose findings are important to those with closely related research interests**\n* Quality of written English: **Needs some language corrections before being published**\n* Quality of figures: **- Acceptable**\n* Statistical review: **- No, the manuscript does not need to be seen by a statistician**\n* Declaration of competing interests: **I declare that I have no competing interests。**\n* I agree to the open peer review policy of the journal. I understand that my name will be included on my report to the authors and, if the manuscript is accepted for publication, my named report including any attachments I upload will be posted on the website along with the authors' responses. I agree for my report to be made available under an Open Access Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0/). I understand that any comments which I do not wish to be included in my named report can be included as confidential comments to the editors, which will not be published.: **\nI agree to the open peer review policy of the journal**\n* Were you mentored through this peer review?: **No**\n"},{"type":"reviewerAgreed","content":"","date":"2021-01-23T00:00:00+00:00","index":4,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-01-22T00:00:00+00:00","index":3,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-01-19T01:00:00+00:00","index":2,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-01-19T00:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2021-01-19T00:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-09-11T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-08-27T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-07-11T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d7be46c2-1611-40f1-aaae-85d42073d296","owner":[],"postedDate":"August 28th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":382828,"name":"Translational Medicine"},{"id":382829,"name":"Internal Medicine"},{"id":382830,"name":"Integrative \u0026 Complementary Medicine"}],"tags":[],"updatedAt":"2021-07-27T21:07:25+00:00","versionOfRecord":{"articleIdentity":"rs-35085","link":"https://doi.org/10.1186/s13063-021-05247-z","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2021-04-20 21:07:25","publishedOnDateReadable":"April 20th, 2021"},"versionCreatedAt":"2020-08-28 15:22:26","video":"","vorDoi":"10.1186/s13063-021-05247-z","vorDoiUrl":"https://doi.org/10.1186/s13063-021-05247-z","workflowStages":[]},"version":"v1","identity":"rs-35085","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-35085","identity":"rs-35085","version":["v1"]},"buildId":"cBFmMYwuxLRRLfASyISRj","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}