Open Access Protocol BMJ Open: first published as 10.1136/bmjopen-2016-011732 on 8 September 2016. Downloaded from Efficacy and safety of Postoperative Intravenous Parecoxib sodium Followed by ORal CElecoxib (PIPFORCE) post- total knee arthroplasty in patients with osteoarthritis: a study protocol for a multicentre, double-blind, parallel- group trial Qianyu Zhuang,1 Yanyan Bian,1 Wei Wang,1 Jingmei Jiang,2 Bin Feng,1 Tiezheng Sun,3 Jianhao Lin,3 Miaofeng Zhang,4 Shigui Yan,4 Bin Shen,5 Fuxing Pei,5 Xisheng Weng1 To cite: Zhuang Q, Bian Y, ABSTRACT Strengths and limitations of this study Wang W, et al. Efficacy and Introduction: Total knee arthroplasty (TKA) has been safety of Postoperative regarded as a most painful orthopaedic surgery. ▪ Intravenous Parecoxib This is the first study to investigate the efficacy Although many surgeons sequentially use parecoxib sodium Followed by ORal and safety of the sequential analgesia regimen of CElecoxib (PIPFORCE) post- and celecoxib as a routine strategy for postoperative intravenous parecoxib followed by oral celecoxib total knee arthroplasty in pain control after TKA, high quality evidence is still after total knee arthroplasty surgery. patients with osteoarthritis: a lacking to prove the effect of this sequential regimen, ▪ This study will explore the benefits of prolonged study protocol for a especially at the medium-term follow-up. The purpose sequential treatment of parecoxib and celecoxib multicentre, double-blind, of this study, therefore, is to evaluate efficacy and in medium-term function recovery. parallel-group trial. BMJ safety of postoperative intravenous parecoxib sodium ▪ The results will promote the non-steroidal Open 2016;6:e011732. followed by oral celecoxib in patients with anti-inflammatory drugs incorporation into the http://bmjopen.bmj.com/ doi:10.1136/bmjopen-2016- osteoarthritis (OA) undergoing TKA. The hypothesis is 011732 standard multimodal analgesic regimen for post- that compared to placebo with opioids as rescue operative pain control. treatment, sequential use of parecoxib and celecoxib ▪ Potential limitations include the need for further ▸ Prepublication history for can achieve less morphine consumption over the validation studies from other institutions outside this paper is available online. postoperative 2 weeks, as well as better pain control, China, lack of investigation of the long-term (eg, To view these files please quicker functional recovery in the postoperative >3 months) effects of the sequential treatment, visit the journal online 6 weeks and less opioid-related adverse events during (http://dx.doi.org/10.1136/ and compromise of the test accuracy of synovial the 12-week recovery phase. bmjopen-2016-011732). fluid cytokines. Methods and analysis: This study is designed as a on September 24, 2021 by guest. Protected copyright. Received 7 March 2016 multicentre, randomised, double-blind, parallel-group Revised 29 July 2016 and placebo-controlled trial. The target sample size is Accepted 11 August 2016 246. All participants who meet the study inclusion and Peking Union Medical College Hospital, China (Protocol exclusion criteria will be randomly assigned in a 1:1 number: S-572) Study results will be available as ratio to either the parecoxib/celecoxib group or placebo published manuscripts and presentations at national group. The randomisation and allocation will be study and international meetings. site based. The study will consist of three phases: an Trial registration number: NCT02198924. initial screening phase; a 6-week double-blind treatment phase; and a 6-week follow-up phase. The primary end point is cumulative opioid consumption during 2 weeks postoperation. Secondary end points INTRODUCTION For numbered affiliations see consist of the postoperative visual analogue scale end of article. score, knee joint function, quality of life, local skin Osteoarthritis (OA) is a chronic degenerative temperature, erythrocyte sedimentation rate, C reactive joint disorder which frequently occurs in the protein, cytokines and blood coagulation parameters. elderly.12In mainland China, knee OA is Correspondence to Dr Xisheng Weng; Safety end points will be monitored too. the leading cause of disability in elderly wengxishengpumch@126. Ethics and dissemination: Ethics approval for this patients. Total knee arthroplasty (TKA) is com study has been obtained from the Ethics Committee, now generally regarded as an effective Zhuang Q, et al. BMJ Open 2016;6:e011732. doi:10.1136/bmjopen-2016-011732 1 Open Access BMJ Open: first published as 10.1136/bmjopen-2016-011732 on 8 September 2016. Downloaded from treatment for end-stage knee OA in pain alleviation, AIM AND OBJECTIVES joint deformity correction and life quality Primary objectives improvement.34 The primary objective of this study is to evaluate the However, TKA has been regarded as a most painful morphine-sparing effects of the sequential treatment orthopaedic surgery due to the weight-bearing with parecoxib and celecoxib versus placebo in partici- characteristics of knee joint and the high demand for pants undergoing TKA. functional exercise within 6–8 weeks postoperation.56 First, TKA induces massive tissue damage and severe Secondary objectives perioperative pain which jointly hamper early post- ▸ To compare the effects of the sequential treatment operative rehabilitation and exert negative effects on sur- versus placebo on pain relief, inflammation control 7 gical outcome and patient satisfaction. Second, and functional rehabilitation after TKA. postoperative pain, as the most suffering experience for ▸ To compare the safety of the sequential treatment patients with TKA, may prolong postoperative bedbound versus placebo post-TKA. duration and increase the risks for pulmonary infection, deep venous thrombosis (DVT), pulmonary embolism (PE), etc.8 Third, previous findings suggested that local DESIGN AND METHODS inflammation triggered by tissue damage increases the Study design central and peripheral pain sensitivity, as well as leads to This study is an investigator initiated postmarketing acute haemorrhage and swelling, which poses greater study which is designed as multicentre, randomised, challenges to the postoperative rehabilitation.910 double blind, parallel-group, and placebo-controlled. The targeted treatment with a selective cyclooxygenase (COX-2) inhibitor, such as parecoxib or celecoxib, can Study setting significantly reduce the inflammatory reaction level This study is being conducted by Peking Union Medical – within 2 days postoperation.11 14 In addition, periopera- College Hospital, China as the coordinating centre and tive administration of celecoxib can relieve postoperative three other participating centres including (1)West pain and improve articular function, thereby improving China Hospital of Sichuan University, Sichuan Province, the life quality of the patients. Recently, sequential China, (2) People’s Hospital of Peking University, therapy of intravenous-to-oral COX-2 inhibitor adminis- Beijing, China and (3)Second Affiliated Hospital of tration has been demonstrated as effective in many post- Zhejiang University College of Medicine, Zhejiang – operative pain control models.15 19 Significant Province, China. morphine sparing effect and reduction of opioid-related – complications were also observed.15 19 In China, it is Study participants becoming a routine at many institutions that 40 mg pare- Inclusion criteria http://bmjopen.bmj.com/ coxib be administered intravenously two times a day for Participant eligibility should be reviewed and documen- the first 3 days after surgery, followed by 200 mg cele- ted by an appropriately qualified member of the investi- coxib administered orally two times a day for 2 weeks or gator’s study team before participants are included in longer. Although satisfactory results of the sequential the study. therapy on short-term pain alleviation and functional Participants must meet all of the following inclusion cri- recovery have been preliminarily observed in clinical teria to be eligible for enrolment into the study: practice, high-quality evidence is still lacking, especially 1. The participant is scheduled to undergo elective at the medium-term/long-term follow-up. unilateral TKA because of OA, performed under a on September 24, 2021 by guest. Protected copyright. The Postoperative Intravenous Parecoxib Sodium standardised regimen of general anaesthesia, as spe- Followed by ORal CElecoxib (PIPFORCE) study (Trial cified in this protocol. registration number: ClinicalTrails.gov identifier: 2. Evidence of a personally signed and dated informed NCT02198924) aims to investigate the sequential anal- consent document indicating that the participant gesia regimen with intravenous parecoxib followed by (or a legal representative) has been informed of all oral celecoxib for postsurgical analgesic treatment in pertinent aspects of the study. patients with OA undergoing TKA surgery. Participants 3. The participant is a male or female over 18 years of will receive a double-blinded study medication consisting age. of parecoxib injection in analgesic doses or matching 4. Male and female participants of childbearing poten- placebo followed by oral celecoxib in acute pain doses tial must agree to use an effective method of contra- or matching placebo. The hypothesis is that participants ception throughout the study and for 42 days after treated with parecoxib/celecoxib will consume less mor- the last dose of assigned treatment. A participant is phine during the postoperative