Extracorporeal shockwave therapy with a modified peppering technique for knee osteoarthritis: study protocol for a randomized controlled trial

Huei-Yu Lo, Huan-Jui Yeh, , Kun-Dong Ho,

1 Department of Physical Medicine and Rehabilitation, Taoyuan General Hospital, Ministry of Health and Welfare, Taoyuan, Taiwan,China

2 Institute of Public Health, National Yang-Ming University, Taipei, Taiwan, China

INTRODUCTION

Knee osteoarthritis (OA) is a common disease that causes joint pain, stiffness, and movement limitation. Nearly 50% of those aged 75 years and above are affected.1Current and typical guidelines for conservative treatment of symptomatic knee osteoarthritis include exercise,anti-inflammatorydrugs,2,3transcutaneous electrical nerve stimulation, and magnetic fields.4,5These treatments that have been evaluated reduce pain and improve the patient’s quality of life, while the efficacy of these treatments is not yet satisfied.

Besides the traditional treatments, prolotherapy is an injection therapy stimulating local healing. Current studies demonstrated clinical benefit for pain and improvement of function in patients with mild-to-moderate symptomatic knee osteoarthritis.6-9The effects of multi-point injections were more pronounced in several studies than single-point injection.7,9,10The key principle of prolotherapy is injected a small volume of an irritant solution at injured tendonand ligament insertion, and in adjacent joint space.11Current mechanisms of prolotherapy including fibroblast and vascular proliferation and collagen deposition have been shown to increase ligament thickness, energy absorption,and load bearing, based on animal studies.12,13However,the injection is an invasive intervention resulting in pain and bleeding. Many patients had post-injection pain during the first 72 hours after injections, and some of them required treatment with medication.8

Since the 1980s, extracorporeal shockwave therapy(ESWT), a non-invasive therapy originally treated kidney stone, has been widely used for musculoskeletal disorders.Based on the results of animal studies, ESWT promoted tissue regeneration by improving blood supply and increasing cell proliferation.14In recent years, studies had investigated the efficacy of ESWT in knee osteoarthritis.They determined that ESWT is effective in pain relief and functional improvement in OA patients.15,16However, they did not establish a treatment protocol for ESWT.To avoid common side-effects of invasive interventions and oral medications, we apply the multi-point concept of prolotherapy to ESWT. The concept is treating tendon and ligament insertions that can promote tissue regeneration effectively. Meanwhile, taking advantage of noninvasive therapy,17we design a randomized control trial study.This study aims to investigate the effects of ESWT with modified peppering technique over ligament and tendon attachments in patients with knee OA.

METHODS/DESIGN

Study design

This is a prospective, single-center, double-blind, randomized controlled trial. We will enroll at least 36 patients with knee OA. This prospective and randomized study aims to compare the efficacy of shockwave with modified peppering method and tender point method in patients diagnosed with knee OA. The protocols follow the guiding principles of the Declaration of Helsinki, and applicable local laws and regulations. The experiments were approved by the Ethics Committee, Taoyuan General Hospital,Ministry of Health and Welfare, Taiwan, China (IRB No.TYGH105013). All patients will sign the informed consent.ClinicalTrial.gov identifier: NCT03048773. The patients will randomly receive ESWT or sham ESWT. A schedule of enrolment, interventions and assessments is shown in

Table 1: Schedule of outcome assessments

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Table 1. Trial flow chart is exhibited in Figure 1. This protocol was written following the Standard Protocol Items:Recommendations for Interventional trials (SPIRIT)checklis18(Additional file 1).

Participants

Patients were recruited from Rehabilitation Outpatient Department, Taoyuan General Hospital, Ministry of Health and Welfare, Taiwan, China from January 1, 2017 to December 31, 2018.

Inclusion criteria

Patients who meet all of the following criteria will be considered for study inclusion:

? Accordance with American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee19

Figure 1: Trial flow chart.

? Kellgren- Lawrence grading scale, grade 2 to grade 4

? Suitable for shockwave therapy and physical therapy with (transcutaneous electrical nerve stimulation +magnetic fields + stretching + strengthening exercise)

? Visual analog scale (VAS) ≥ 4

? Age 20-100 years

Exclusion criteria

Patients who meet one or more of the following conditions will be excluded from the study:

? Not suitable for shockwave therapy, including acute infection, osteomyelitis, coagulopathy, use of anticoagulants, pregnant women, patients with a pacemaker or implantable cardiac defibrillator

? The patient who cannot understand Chinese, including aphasia or dementia

? The patient who cannot receive four weeks of therapy

? The patient who cannot walk due to peripheral neuropathy or central nerve system diseases

? Total knee arthroplasty

? Shockwave therapy of knee for the prior 3 months

? Skin defect or soft tissue infection over the symptomatic knee

? Other causes of knee pain which cannot be treated with physical therapy, including rheumatoid arthritis, infection, fracture, or ligament disruption

Randomization and blinding

Participants will be randomly assigned into two groups(shockwave or sham shockwave) using a computergenerated randomization scheme by the professional statisticians who do not participate in this trial from the Taoyuan General Hospital. All patients will be blind to therapeutic method until the end of follow-up. The implementers will not be blind to the treatment. The results will be evaluated by independent researchers who are blind to therapeutic method.

Intervention

ESWT will be performed on the 1stweek, 2ndweek and 3rdweek. The operators will examine the knee, mark eight major tendon and ligament insertions (quadriceps tendon,patellar tendon ×2, medial collateral ligament ×2, lateral collateral ligament ×2, and pes anserinus) (Figure 2). We will treat at each ligament-bone and tendon insertion using a modified peppering technique (that is a shockwave probe which is moved over an area of approximately 4 cm2slowly in a circular manner) with 20 mm penetration depth applicator. The patient will be kept in a supine position with treated knee flexion approximately 90°. ESWT will be performed with piezoelectric shockwave. Jelly will be applied to the skin, and the applicator will be put into the eight insertion sites with an energy flux density of 0.24 mJ/mm2and 1600 pulses. In the sham ESWT group,patients will receive 1600 pulses of shockwave at 0.24 mJ/mm2in the same area without jelly between applicator pad and hand piece. After the treatment, participants will be advised to relative knee rest for 1 to 2 days with the progressive resumption of daily activity over one week.All their medications will be recorded during the trial.

Participants will receive transcutaneous electrical nerve stimulation, magnetic fields and knee exercises demonstrated by a physical therapist (3 times per week for 1 month). Participants will be advised to begin exercises and to increase therapy as tolerated over one month gradually and to continue them after that if patients desire.

Outcome measures Primary outcome measure

Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) after 3 weeks of treatment and 1 week after treatment: The WOMAC, a validated disease-specific self-reporting questionnaire, is an examination for evaluating OA symptoms.

Secondary outcome measures

VAS and 6-minute walk test (6MWT) after 3 weeks of treatment and 1 week after treatment: The VAS scores are based on pain intensity, where 0 and 10 points represent an absence of pain and a maximal intensity level of pain,respectively.20The 6MWT is used to measure walking ability in patients with knee OA, and measure the distance walked in meters over 6 minutes.21,22

Incidence of adverse events after 3 weeks of treatment and 1 week after treatment.

Adverse events

Figure 2: Eight major tendon and ligament insertions marked by the operator when the knee is examined.

ESWT may produce moderate or severe pain, and patients may take analgesics prescribed by the doctor.

The assessment scale used in this trial has been used multiple times. There is no absolute correlation between the risk of mental discomfort during the writing process or afterwards. If the patients feel any discomfort during the questionnaire filling or answering process, they may terminate the trial at any time. 6MWT may result in physical discomfort of lower extremity fatigue. The trial may be terminated at any time during the test and we will provide complete follow-up medical care.

Withdrawal criteria

The patients will meet the conditions for inclusion in this study. During the trial, they can withdraw from this test at any time if they feel unstable physiological conditions(including acute infection or surgery).

? The patient is free to decide whether to participate in the trial. The consent can be withdrawn at any time during the trial without any reason, and the withdrawal will not cause any unpleasantness or affect the future doctor’s care for patients. The principal investigator may also suspend the trial if necessary.

? If the patient withdraws from this trial early, whenever he/she withdraws, for the safety, the patient will be scheduled to undergo a related physical examination or other necessary tests to assess his/her physical condition.

Data management

A summarized table will be developed to record the data.The data will be transferred to an electronic format using a double-data entry strategy. The database will be locked by the researcher in charge and will not be altered. All information relating to this trial will be preserved by Taoyuan General Hospital, Taiwan, China. An outcome analysis report will be made by the professional statistician.

Monitoring

The trial process and the data will be monitored by the researcher with full access to all documents, ensuring patient safety and complete data.

Sample size

We intend to recruit at least 36 participants based on the estimate that a sample of 18 participants per group would provide 80% power of detecting a treatment effect, with the potential for a significance level of 0.05. This is based on the hypothesis that ESWT would improve the primary outcome (total WOMAC score) by 40%, and the sham treatment would result in no improvement.

Statistical analysis

The analysis will be performed on the basis of the intention-to-treat principle. The interim analysis will not be used. All data will be analyzed using SPSS 19.0 software(SPSS, Chicago, IL, USA) by a statistician.

All baseline data will be analyzed using descriptive statistics. For the categorical variables, the difference in the incidence of adverse events will be compared using chisquare test or Fisher’s exact test. For continuous variables,intergroup differences in the VAS scores and the WOMAC and 6MWT results will be compared using independent sample t-tests or Mann-Whitney U tests.

Ethics and dissemination Ethics

This study protocol acquired written approval from Ethics Committee, Taoyuan General Hospital, Ministry of Health and Welfare, Taiwan, China (IRB No. TYGH105013) and will be performed in accordance with the Declaration of Helsinki developed by the World Medical Association.Each patient will be informed about participation in the trial by the researchers or researcher-authorized physicians. Written informed consent will be obtained from each patient.

Dissemination

Recruitment began on January 1, 2017, and will be finished on December 31, 2018. Data will be collected on January 31, 2019.

The results of the trial will be reported in a scientific conference or disseminated in a peer-reviewed journal.The author’s name will be individuals who have made a critical contribution to the study design and implementation, based on Unified Requirements for Submission of Biomedical Journals.

Compensation and insurance

In accordance with the clinical trial plan set out in this study, the trial center will provide professional medical care and medical consultation if adverse reactions or damages related to the trials occur. Patients do not have to bear the necessary medical expenses for treating adverse reactions or injuries.

Confidentiality

The test execution agency will consider any identifiable patient record and personal privacy information as confidential and will not be disclosed. The patient understands that the signing of this consent form allows the original medical record to be directly reviewed by the monitor,auditor, research ethics committee and the competent authority to ensure that the clinical trial process and data are in compliance with relevant laws and regulations.

Even if the test results are published, the patient’s identity will remain confidential.

DISCUSSION

The experiment is expected to have the following results:ESWT is effective in improving the pain, stiffness, and functional limitations of degenerative knee joints, improving the patient’s quality of life, and reducing the use of painkillers.

Additional file

Additional file 1: SPIRIT checklist.

Acknowledgments

We thank Ying-Po Hsu and Ruo-Yan Wu for their helps in performing outcome measurements.

Author contributions

HYL and HJY conceived the study and HYL wrote the draft protocol. HYL and KDH designed the study and reviewed the protocol critically for intellectual content. KDH wrote the paper.All authors have read and approved the final protocol.

Conflicts of interest

All authors declare there is no competing interest in research conduction and paper writing.

Financial support

This work was supported by a grant from the Taoyuan General Hospital, No. PTH10603. The funder has no involvement in the study design; data collection, management, analysis, and interpretation; paper writing; or decision to submit the paper for publication.

Institutional review board statement

This study protocol acquired written approval from the Ethics Committee of Taoyuan General Hospital, Ministry of Health and Welfare, Taiwan, China (IRB No. TYGH105013), and will be performed in accordance with the Declaration of Helsinki.

Declaration of patient consent

The authors certify that they will obtain all appropriate patient consent forms. In the form the patients will give their consent for clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity.

Reporting statement

This study follows the Consolidated Standards of Reporting Trials (CONSORT) statement and Standard Protocol Items:Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of Taoyuan General Hospital, Ministry of Health and Welfare, Taiwan, China.

Copyright transfer agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

The individual participant data are available. Individual participant data that underlie the results reported in this article,after deidentification will be shared. The Study Protocol will be available. The data will be available, beginning 3 months and ending 5 years following article publications. Investigations whose proposed use of the data have been approved by an independent review committee (“l(fā)earned intermediary”) identified for this purpose. The shared data will be used for individual participant data meta-analysis. Proposals should be directed to hkundong@gmail.com. To gain access, data requestors will need to sign a data access agreement.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Open access statement

This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

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