Efficacy and Safety of Postoperative Intravenous Parecoxib Sodium Followed by Oral Celecoxib in Osteoarthritis Patients

Overview

In mainland China, knee Osteoarthritis (OA) is the leading cause of disability in older persons. Total knee arthroplasty (TKA) is now generally regarded by orthopaedic surgeons and patients as an effective treatment for end-stage knee OA in order to relieve pain, correct joint deformity and improve the life quality of patients.However, TKA has been called as one of the most painful Orthopedics surgery due to the weight bearing characteristics of knee joint and the high demand of functional exercise within the 6-8 weeks post operation. The targeted application of selective cyclooxygenase (COX) -2 inhibitor, such as Parecoxib or Celecoxib, can significantly reduce the level of inflammatory reaction one and two days postoperation . In addition, the perioperative administration of Celecoxib can directly or indirectly relieve postoperative pain, improve articular function and eventually augment life quality of the patients . Recently, effective treatment of post-operative pain with intravenous followed by oral COX-2 specific inhibitor has been demonstrated in many post-operative pain models . Significant morphine sparing effect and reduction of opioid distressed symptoms were also observed. In China, many surgeons have accept it as a routine strategy for controlling pain post TKA to sequentially give parecoxib 40 mg intravenously twice daily for the first 3 days post surgery and then Celecoxib 200mg orally twice daily. Although satisfactory results of this combination treatment on short-term pain reduction and functional improvement has been observed in clinical practice, high quality evidence is still lacking to prove its effect on the medium or long-term functionality recovery. This study is being conducted to investigate the combination regimen with intravenous parecoxib followed by oral celecoxib for post-surgical analgesic treatment in osteoarthritis patients undergoing total knee arthroplastic (TKA) surgery. Subjects will receive double-blinded study medication consisting of parecoxib injection in analgesic doses or matching placebo followed by oral celecoxib in acute pain doses or matching placebo in a double-blinded fashion. The hypothesis is subjects treated with parecoxib/celecoxib will consume less morphine over the first 24 hours of postoperation period, achieve improved pain control over study period, a quicker return to functionality, and has less opioid adverse events than those treated with opioids alone over 6-week recovery phase.

Total knee arthroplasty (TKA), though generally regarded as an effective treatment for end-stage knee OA, has been called as "one of the most painful orthopedics surgeries" due to the weight bearing characteristics of knee joint and the high demand of functional exercise within the 6-8 weeks post operation. Parecoxib and Celecoxib have been found to be able to relieve postoperative pain, spare opioid use, improve articular function and eventually augment life quality of the patients after TKA. In China, therefore, many surgeons have accept it as a routine strategy for controlling pain post TKA to sequentially use Parecoxib and then Celecoxib. However, high quality evidence is still lacking to prove its effect on the medium or long-term functionality recovery. This multicenter, double blind, parallel-group randomized study, therefore, is aiming to evaluate efficacy and safety of postoperative intravenous Parecoxib sodium followed by oral Celecoxib in OA patients undergoing TKA. The hypothesis is that compared to placebo with opioids as rescue treatment, sequential use of Parecoxib/Celecoxib can achieve not only less morphine consumption over postoperatively 2 weeks, but also better pain control, quicker functional recovery, and less opioid related adverse events over 6-week recovery phase. The primary objective of this study is to evaluate the morphine-sparing effects of the combination treatment with Parecoxib and Celecoxib versus placebo in subjects undergoing TKA. The secondary objective is to compare the effects of the combination treatment versus placebo on pain relief, inflammation control and functional rehabilitation after TKA. Total 86 subjects per group would have 90% power in detecting 100 mg or more in mean difference of morphine use on Day 14 between the two groups, assuming a common standard deviation of 200, and a two-sided alpha level of 0.05. This would result in a total 172 subjects. In consideration of 30% drop outs, 246 subjects would be adequate for the study. All subjects who meet the study inclusion and exclusion criteria will be randomly assigned in a 1:1 ratio to either Parecoxib/Celecoxib group or placebo group. The allocation or randomization will be study site based.Data will be collected using an Electronic Data Capture (EDC) under a strict intent-to-treat methodology, i.e., all the data of any Inform Consent Form signed subjects will be included in the study database.All subjects will be recruited from 4 study centers in China. The study will consist of 3 phases: an initial screening phase which must be completed within 30 days prior to randomization; a 6-week double blind treatment phase; and a 6 week follow up phase. A two-week wash-out procedure will be required before randomization for the patients with previous use of nonsteroidal antiinflammatory drug (NSAID) or COX-2 specific inhibitors.Variables considered continuous will be presented by descriptive statistics: number, mean, standard deviation, median, minimum, and maximum; and analyzed using parametric or non-parametric ANOVA, as appropriate. Variables considered categorical will be tabulated by frequency counts and percentages; and analyzed using Chi-square test or Fisher's exact tests. All the statistical tests will be two-sided with alpha=0.05, i.e., a p value \<= 0.05 would be considered statistically significant.