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    Effectiveness and safety of celecoxib combined with diacerein in the treatment of senile degenerative knee osteoarthritis:study protocol and preliminary results of a randomized controlled trial

    2017-04-09 07:07:15GuodongWangLingyunYangBinHeYunhuaWangQiChenLeiFan

    Guo-dong Wang, Ling-yun Yang, Bin He*, Yun-hua Wang, Qi Chen, Lei Fan

    Department of Orthopedics, Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China

    INTRODUCTION

    Knee osteoarthritis, also known as knee degenerative arthritis, commonly occurs in older adults. It is pathologically characterized by degeneration of the knee cartilage and clinically manifested as knee pain and stiffness and limited mobility of the knee joint. The objective of treatment is to reduce pain, improve joint movement, and prevent further damage to the joint.1-6

    The selective cyclooxygenase-2 inhibitor celecoxib is the most commonly used non-steroidal anti-in flammatory drug for the treatment of knee osteoarthritis. It carries a low risk of stomach and intestinal adverse reactions and has a rapid onset of action. However, it cannot prevent the occurrence and development of knee osteoarthritis. Celecoxib withdrawal is likely to induce a rebound increase in in flammation that may aggravate symptoms.7-10Diacerein,a drug used to improve articular cartilage metabolism, can postpone the progression of senile degenerative knee osteoarthritis and can compensate for the drawbacks of celecoxib.However, it has a slow onset of action.11-14Therefore, both celecoxib and diacerein have limited curative effects on senile degenerative knee osteoarthritis when used alone.

    In this study, we aim to investigate the curative effects and safety of celecoxib combined with diacerein on senile degenerative knee osteoarthritis and to determine the analgesic and anti-in flammatory effects of the combined therapy.

    METHODS/DESIGN

    Study design

    In this prospective, single-center, randomized controlled study, 300 patients who receive treatment from clinics in the Department of Orthopedics, Second Af filiated Hospital of Nanjing Medical University, China will be included and randomly divided into three groups: celecoxib, diacerein,and celecoxib + diacerein. These patients will be followedup for 36 weeks. The Visual Analogue Scale (VAS) score for pain during the 20-meter walk test and osteoarthritis index will be determined before and 1, 4, 12, 24, and 36 weeks after treatment to investigate the analgesic and anti-in flammatory effects of celecoxib, diacerein, or their combination, with the purpose of identifying the optimal therapeutic approach.

    Figure 1 demonstrates the study flow chart.

    Study setting

    Second Af filiated Hospital of Nanjing Medical University,China.

    Study participants

    A total of 300 patients from the clinics of the Department of

    Strengths and limitations

    · Group randomization will be used. Follow-up results at various time points during a short period of time will be reported.

    · Lack of long-term follow-up results.

    · Simple outcome measures.

    Figure 1: Study flow chart.

    · Small sample size.Orthopedics, Second Af filiated Hospital of Nanjing Medical University, China will be randomly assigned to receive celecoxib and/or diacerein.

    Inclusion criteria

    Patients will be considered for inclusion according to the following criteria:

    · Meet the Guidelines for the Diagnosis and Treatment of Osteoarthritis (2007)15

    · Do not receive other drugs within the preceding 3 weeks

    · Aged over 60 years

    · Provide written informed consent

    Exclusion criteria

    Patients presenting with one or more of the following conditions will be excluded from the study:

    · Other pathological changes in the knee joint, such as tumor, tubercle, or suppuration

    · Metabolic bone disease

    · Acute injury

    · Rheumatoid arthritis

    · Gout

    · Knee trauma

    Withdrawal criteria

    Patients presenting with one or more of the following conditions will be withdrawn from the study:

    · Do not receive the prescribed medication(s), and therapeutic effects cannot be determined

    · Incomplete follow-up data that affect the assessment of curative effects or safety

    Recruitment

    Patients who receive treatment in the clinics of the Second Af filiated Hospital of Nanjing Medical University, China will be invited to voluntarily participate in the trial after reading the recruitment information on the hospital bulletin board and having contact with the responsible researcher via telephone. Only eligible participants will be included after signing informed consent forms.

    Randomization and blinding

    A table of random numbers will be generated by the first author using SPSS 20.0 software (IBM, Armonk, NY, USA).The included 300 patients will be randomly divided into three groups with 100 patients in each group, according to the table of random numbers. Grouping will be not blinded.

    Interventions

    Patients in the celecoxib group will receive celecoxib(P fizer Inc., New York, NY, USA, National Drug Approval Number J20080059; 200 mg, once a day, orally). Patients in the diacerein group will receive diacerein (Kunming Jida Pharmaceutical Co., Ltd., China; National Drug Approval Number J20060017; 50 mg, twice a day, orally). Patients in the celecoxib + diacerein group will receive celecoxib(200 mg, once a day, orally) and diacerein (50 mg, twice a day, orally). Patients in each group will be treated for 12 successive weeks.

    Effectiveness evaluation

    Primary outcome measure

    -The VAS score for pain during the 20-meter walk test before and 1, 4, 12, 24, and 36 weeks after treatment. A selfmade vernier caliper will be used. It contains two sides. The front side will be labeled with the numbers 0–10, with equal distance between digits. The back side will be segmented numerically (0–10; accuracy in millimeters) as the VAS,with 0 indicating no pain at all and 10 suggesting worst pain imaginable.16Each patient will be asked to mark his pain level on the front side. Then, the physician can de fine the patient’s pain according to the digit on the back side that corresponds with the patient’s marked number.

    Secondary outcome measures

    -Osteoarthritis index before and 1, 4, 12, 24, and 36 weeks after treatment

    The osteoarthritis index is used to evaluate the severity of arthritis and the therapeutic effect according to patient’s symptoms and signs.17It is used to evaluate the structure and function of the hip and knee from the perspectives of pain, stiffness, and physical function. The whole section or portions of it can be selected for use. The VAS score can be used to evaluate osteoarthritis. Higher score indicates more severe osteoarthritis.

    - X-ray image findings of the knee before and 1, 4, 12, 24,and 36 weeks after treatment

    X-ray image findings of the knee will help evaluate morphological changes after treatment.

    - Incidence of adverse events 1, 4, 12, 24, and 36 weeks after treatment

    Incidence of adverse events will be used to evaluate drug safety. The incidence of adverse events = number of patients having adverse events/total number of patients × 100%.

    Timing of primary and secondary outcome measures

    Table 1 shows the timing of measurements of the primary and secondary outcome measures.

    Safety evaluation

    During the follow-up period, drug-related adverse events,including nausea, vomiting, dizziness, headache, and joint stiffness, will be recorded. The possible cause of adverse events will be analyzed. Data on patient’s adverse events and side effects will be tabulated. The causes and explanations will be reported. These adverse events and side effects as well as their causes and explanations will be reported to the researchers in charge and the ethics committee of the clinical research institute within 24 hours.

    Audits

    Initial stage

    The study protocol should be approved by the Ethics Committee of the Second Af filiated Hospital of Nanjing Medical University of China, and a protocol agreement should be signed.

    Table 1: Outcome measures and timing of the measurements

    Table 2: Patients’ baseline data

    During the trial

    During participant recruitment, regular audits will be necessary to ensure included participants are eligible, the trial is performed in strict accordance with the study protocol,and related data are complete.

    Final stage

    At the end of all trial procedures, a final visit will be required to ensure relevant records are complete and accurate.

    Statistical analysis

    Statistical design, methods, and analysis principle

    All data will be statistically analyzed using SPSS 20.0 software (IBM, Avmonk, NY, USA) and follow the intention-totreat principle. Normally distributed measurement data will be expressed as the mean ± standard deviation. Non-normally distributed measurement data will be expressed as lower quartile (q1), median, and upper quartile (q3). Numerical data will be expressed as percentage. Repeated measures analysis of variance will be used for comparisons of VAS score for pain during the 20-meter walk test and osteoarthritis index between pre-treatment and 1, 4, 12, 24, and 36 weeks after treatment. One-way analysis of variance and the Least Signi ficant Difference test will be used for comparisons of VAS score for pain during the 20-meter test and osteoarthritis index among the celecoxib, diacerein, and celecoxib + diacerein groups at the same time point. Pearson’s chi-square test will be used for comparison of the incidence of adverse events among the three groups at the same time point. An α= 0.05 (two-sided) will be used for inspection level.

    Sample size

    In accordance with our experience, we hypothesize that the VAS score for pain during the 20-meter walk test in the celecoxib + diacerein and celecoxib groups would be reduced by 3 and 4 points, respectively, compared to pre-treatment.Taking β = 0.1, power = 90%, and α = 0.05 (two-sided),the final effective sample size of n = 133 per group was calculated. Assuming a patient loss rate of 20%, we require 160 patients per group. At the end of expected recruitment,at least 100 patients per group will be included.

    Processing method for missing data

    If a patient’s records are lost, the patient will be excluded from this study. Corresponding numbers of new cases will be supplemented.

    Baseline data collection

    Table 2 shows baseline data of patients who will be included in this study.

    Data management

    Researchers will complete the case report form for each case. After the completed case report form is reviewed by an inspector, data input and management will be performed.After data transfer, contents recorded in the case report form will not be modi fied.

    Quality control of the clinical trial

    During the clinical trial, sponsor inspectors should conduct regular periodic visits to the research center to ensure strict adherence to all aspects of the research program. In addition,the original data will be checked to ensure that the contents of the case report forms are correct and complete.

    Ethical considerations and informed consent

    This clinical trial follows the relevant laws and regulations of the Declaration of Helsinki. This manuscript is prepared and modi fied according to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines (Additional File 1). The researchers take the responsibility of providing the independent ethics committee with the clinical trial protocol and informed consent forms and providing patients with related informational materials. The trial will not be initiated until approval from the ethics committee is received. This study was approved by the Ethics Committee of the Second Af filiated Hospital of Nanjing Medical University of China (approval No. (2017) KY-091).

    RESULTS

    Preliminary experimental results of 210 patients were reported at the time of submission. These results revealed that at 1 week after treatment, the VAS score for pain during the 20-meter walk test and osteoarthritis index were signi ficantly decreased in the celecoxib group (n = 70) and celecoxib+ diacerein group (n = 70) compared to pre-treatment (P <0.01). At 4 and 12 weeks after treatment, the VAS score for pain during the 20-meter walk test and osteoarthritis index were signi ficantly decreased in the celecoxib, diacerein, and celecoxib + diacerein groups compared to pre-treatment(P < 0.01). At 24 weeks after treatment, the VAS score for pain during the 20-meter walk test and osteoarthritis index were signi ficantly decreased in the diacerein and celecoxib+ diacerein groups compared to pre-treatment (P < 0.01). In addition, the therapeutic effects were more obvious in the celecoxib + diacerein group than in the diacerein group.18

    DISCUSSION

    Significance of this study

    Celecoxib and diacerein used alone for the treatment of senile degenerative knee osteoarthritis have drawbacks. In this study, these two drugs will be prescribed together in order to provide complementary effects to delay the progression of senile degenerative knee osteoarthritis, reduce pain, and achieve long-lasting effects. This will provide a new solution for the clinical treatment of senile degenerative knee osteoarthritis.19,20

    Limitations of this study

    There are several limitations of this study. First, outcome measures are relatively simple; second, blinding will not be used; and third, a placebo control group will not be included.All these will in fluence the accuracy of clinical outcomes and will be addressed in future studies.

    Evidence for contribution to future studies

    Preliminary experimental results con firmed that the combination of celecoxib with diacerein for the treatment of senile degenerative knee osteoarthritis is superior to monotherapy in terms of curative effects and safety; in particular, early analgesic and long-lasting effects were observed. In this study, a larger sample size will be included and longer follow-up will be performed to demonstrate de finitive clinical evidence to support the conclusion made in the preliminary experiment and facilitate popularization of this treatment protocol in the near future.

    Author contributions

    GDW and LYY conceived and designed the entire study and wrote and reviewed the article. BH provided constructive suggestions.YHW and QC will assist LF in performing the trial. All authors approved the final version of this article.

    Conflicts of interest

    None declared.

    Research ethics

    The study was approved by the Ethics Committee, Second Af filiated Hospital of Nanjing Medical University of China (approval No. (2017) KY-091). The study will be performed according to theDeclaration of Helsinkiand relevant ethical principles.

    Declaration of patient consent

    The authors certify that they will obtain patient consent forms. In the form, patients will give their consent for their images and other clinical information to be reported in journal(s). The patients will understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

    Data sharing statement

    Datasets analyzed during the current study are available from the corresponding author on reasonable request.

    Plagiarism check

    Checked twice by iThenticate.

    Peer review

    Externally peer reviewed.

    Open access statement

    This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under identical terms.

    Additional file

    Additional file 1: SPIRIT checklist.

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    8. Zhang XL, Yang J, Yang L, et al. Ef ficacy and safety of zhuang gu joint capsules in combination with celecoxib in knee osteoarthritis: a multi-center, randomized, double-blind, double-dummy, and parallel controlled trial.Chin Med J (Engl).2016;129:891-897.

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