<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02198924</url>
  </required_header>
  <id_info>
    <org_study_id>WI1180091</org_study_id>
    <nct_id>NCT02198924</nct_id>
  </id_info>
  <brief_title>Efficacy and Safety of Postoperative Intravenous Parecoxib Sodium Followed by Oral Celecoxib in Osteoarthritis Patients</brief_title>
  <official_title>A Study to Evaluate Efficacy and Safety of Postoperative Intravenous Parecoxib Sodium Followed by Oral Celecoxib Post Total Knee Arthroplasty in Osteoarthritis Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Peking Union Medical College Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Peking Union Medical College Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In mainland China, knee Osteoarthritis (OA) is the leading cause of disability in older&#xD;
      persons. Total knee arthroplasty (TKA) is now generally regarded by orthopaedic surgeons and&#xD;
      patients as an effective treatment for end-stage knee OA in order to relieve pain, correct&#xD;
      joint deformity and improve the life quality of patients.However, TKA has been called as one&#xD;
      of the most painful Orthopedics surgery due to the weight bearing characteristics of knee&#xD;
      joint and the high demand of functional exercise within the 6-8 weeks post operation. The&#xD;
      targeted application of selective cyclooxygenase (COX) -2 inhibitor, such as Parecoxib or&#xD;
      Celecoxib, can significantly reduce the level of inflammatory reaction one and two days&#xD;
      postoperation . In addition, the perioperative administration of Celecoxib can directly or&#xD;
      indirectly relieve postoperative pain, improve articular function and eventually augment life&#xD;
      quality of the patients . Recently, effective treatment of post-operative pain with&#xD;
      intravenous followed by oral COX-2 specific inhibitor has been demonstrated in many&#xD;
      post-operative pain models . Significant morphine sparing effect and reduction of opioid&#xD;
      distressed symptoms were also observed. In China, many surgeons have accept it as a routine&#xD;
      strategy for controlling pain post TKA to sequentially give parecoxib 40 mg intravenously&#xD;
      twice daily for the first 3 days post surgery and then Celecoxib 200mg orally twice daily.&#xD;
      Although satisfactory results of this combination treatment on short-term pain reduction and&#xD;
      functional improvement has been observed in clinical practice, high quality evidence is still&#xD;
      lacking to prove its effect on the medium or long-term functionality recovery. This study is&#xD;
      being conducted to investigate the combination regimen with intravenous parecoxib followed by&#xD;
      oral celecoxib for post-surgical analgesic treatment in osteoarthritis patients undergoing&#xD;
      total knee arthroplastic (TKA) surgery. Subjects will receive double-blinded study medication&#xD;
      consisting of parecoxib injection in analgesic doses or matching placebo followed by oral&#xD;
      celecoxib in acute pain doses or matching placebo in a double-blinded fashion. The hypothesis&#xD;
      is subjects treated with parecoxib/celecoxib will consume less morphine over the first 24&#xD;
      hours of postoperation period, achieve improved pain control over study period, a quicker&#xD;
      return to functionality, and has less opioid adverse events than those treated with opioids&#xD;
      alone over 6-week recovery phase.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Total knee arthroplasty (TKA), though generally regarded as an effective treatment for&#xD;
      end-stage knee OA, has been called as &quot;one of the most painful orthopedics surgeries&quot; due to&#xD;
      the weight bearing characteristics of knee joint and the high demand of functional exercise&#xD;
      within the 6-8 weeks post operation.&#xD;
&#xD;
      Parecoxib and Celecoxib have been found to be able to relieve postoperative pain, spare&#xD;
      opioid use, improve articular function and eventually augment life quality of the patients&#xD;
      after TKA. In China, therefore, many surgeons have accept it as a routine strategy for&#xD;
      controlling pain post TKA to sequentially use Parecoxib and then Celecoxib. However, high&#xD;
      quality evidence is still lacking to prove its effect on the medium or long-term&#xD;
      functionality recovery.&#xD;
&#xD;
      This multicenter, double blind, parallel-group randomized study, therefore, is aiming to&#xD;
      evaluate efficacy and safety of postoperative intravenous Parecoxib sodium followed by oral&#xD;
      Celecoxib in OA patients undergoing TKA. The hypothesis is that compared to placebo with&#xD;
      opioids as rescue treatment, sequential use of Parecoxib/Celecoxib can achieve not only less&#xD;
      morphine consumption over postoperatively 2 weeks, but also better pain control, quicker&#xD;
      functional recovery, and less opioid related adverse events over 6-week recovery phase.&#xD;
&#xD;
      The primary objective of this study is to evaluate the morphine-sparing effects of the&#xD;
      combination treatment with Parecoxib and Celecoxib versus placebo in subjects undergoing TKA.&#xD;
      The secondary objective is to compare the effects of the combination treatment versus placebo&#xD;
      on pain relief, inflammation control and functional rehabilitation after TKA. Total 86&#xD;
      subjects per group would have 90% power in detecting 100 mg or more in mean difference of&#xD;
      morphine use on Day 14 between the two groups, assuming a common standard deviation of 200,&#xD;
      and a two-sided alpha level of 0.05. This would result in a total 172 subjects. In&#xD;
      consideration of 30% drop outs, 246 subjects would be adequate for the study. All subjects&#xD;
      who meet the study inclusion and exclusion criteria will be randomly assigned in a 1:1 ratio&#xD;
      to either Parecoxib/Celecoxib group or placebo group. The allocation or randomization will be&#xD;
      study site based.Data will be collected using an Electronic Data Capture (EDC) under a strict&#xD;
      intent-to-treat methodology, i.e., all the data of any Inform Consent Form signed subjects&#xD;
      will be included in the study database.All subjects will be recruited from 4 study centers in&#xD;
      China. The study will consist of 3 phases: an initial screening phase which must be completed&#xD;
      within 30 days prior to randomization; a 6-week double blind treatment phase; and a 6 week&#xD;
      follow up phase. A two-week wash-out procedure will be required before randomization for the&#xD;
      patients with previous use of nonsteroidal antiinflammatory drug (NSAID) or COX-2 specific&#xD;
      inhibitors.Variables considered continuous will be presented by descriptive statistics:&#xD;
      number, mean, standard deviation, median, minimum, and maximum; and analyzed using parametric&#xD;
      or non-parametric ANOVA, as appropriate. Variables considered categorical will be tabulated&#xD;
      by frequency counts and percentages; and analyzed using Chi-square test or Fisher's exact&#xD;
      tests. All the statistical tests will be two-sided with alpha=0.05, i.e., a p value &lt;= 0.05&#xD;
      would be considered statistically significant.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 2014</start_date>
  <completion_date type="Actual">December 2016</completion_date>
  <primary_completion_date type="Actual">November 2016</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Total narcotic use</measure>
    <time_frame>Post-operative 2 WEEKS</time_frame>
    <description>The sum of the cumulative Morphine consumption over the first 24 hours postsurgical period and the narcotic drug consumption till 72h, 2w post operation will be converted to morphine equivalents. The converting of tramadol to Morphine equivalents is estimated as 150mg Tramadol equals to 10mg of Morphine injection.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Knee Society Score</measure>
    <time_frame>post-operation 6 weeks</time_frame>
    <description>For more than 20 years, The Knee Society's Knee Scoring System (KSS) has served as a simple, objective way to measure a patient's functional ability before and after total knee arthroplasty (TKA). KSS questionnaire generates three domain scores: KSS function score (walking, stairs and use of knee supports), range of motion and KSS score (pain, range of motion and stability) scores.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Western Ontario and McMaster Universities Arthritis(WOMAC) Index</measure>
    <time_frame>prior to operation and at 2w,4w and 6w post operation</time_frame>
    <description>The WOMAC is a widely used, proprietary set of standardized questionnaires to evaluate the condition of patients with knee osteoarthritis , including pain, stiffness, and physical functioning of the joints. A WOMAC test takes about 12 minutes, and is among the most widely used assessments in arthritis research.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Knee Society Score</measure>
    <time_frame>prior to operation and at 2w and 4w post operation</time_frame>
    <description>For more than 20 years, The Knee Society's Knee Scoring System (KSS) has served as a simple, objective way to measure a patient's functional ability before and after total knee arthroplasty (TKA). KSS questionnaire generates three domain scores: KSS function score (walking, stairs and use of knee supports), range of motion and KSS score (pain, range of motion and stability) scores.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total Morphine use</measure>
    <time_frame>over the first 24 hours postsurgical period</time_frame>
    <description>The cumulative Morphine consumption over the first 24 hours postsurgical period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total narcotic use</measure>
    <time_frame>72h, 4w, 6w post operation</time_frame>
    <description>The cumulative Morphine consumption and opioid drug over the first 24 hours postsurgical period.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Visual Analogue Scale</measure>
    <time_frame>prior to operation and at 24h, 48h, 72h, 2w, 4w and 6w post operation</time_frame>
    <description>A Visual Analogue Scale (VAS) is a measurement instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured.&#xD;
Operationally a VAS is usually a horizontal line, 100 mm in length, anchored by word descriptors at each end. The patient marks on the line the point that they feel represents their perception of their current state. The VAS score is determined by measuring in millimetres from the left hand end of the line to the point that the patient marks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>EuroQol (EQ-5D) Score</measure>
    <time_frame>prior to operation and 72h, 2w, 4w and 6w post operation</time_frame>
    <description>EQ-5D is a standard instrument for use as a measure of health outcome. EQ-5D is primarily designed for self-completion by respondents and is ideally suited for use in postal surveys, in clinics and face-to-face interviews. It is cognitively simple, taking only a few minutes to complete. Instructions to respondents are included in the questionnaire.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Knee circumference</measure>
    <time_frame>prior to operation and at 72h, 2w, 4w and 6w post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>skin temperature</measure>
    <time_frame>prior to operation and at 72h, 2w, 4w and 6w post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Erythrocyte sedimentation rate(ESR)</measure>
    <time_frame>prior to operation and at 72h, 2w, 4w and 6w post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>C-Reactive Protein，CRP</measure>
    <time_frame>prior to operation and at 72h, 2w, 4w and 6w post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>interleukin-6 concentration in Synovial fluid</measure>
    <time_frame>0h, 24h and 48h post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>interleukin-8 concentration in Synovial fluid</measure>
    <time_frame>0h, 24h and 48h post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>interleukin-10 Synovial fluid concentration</measure>
    <time_frame>0h, 24h and 48h post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>prostaglandin E2 concentration in Synovial fluid</measure>
    <time_frame>0h, 24h and 48h post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>interleukin-6 concentration in Peripheral blood</measure>
    <time_frame>prior to operation and at 72h, 2w, 4w and 6w post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>interleukin-8 concentration in Peripheral blood</measure>
    <time_frame>prior to operation and at 72h, 2w, 4w and 6w post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>interleukin-10 concentration in Peripheral blood</measure>
    <time_frame>prior to operation and at 72h, 2w, 4w and 6w post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>prostaglandin E2 concentration in Peripheral blood</measure>
    <time_frame>prior to operation and at 72h, 2w, 4w and 6w post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>blood coagulation</measure>
    <time_frame>prior to operation and at 72h, 2w, 4w and 6w post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>The nature, incidence, duration, and severity of adverse events</measure>
    <time_frame>until 6w post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Discontinuation due to adverse events</measure>
    <time_frame>until 6w post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Adverse events</measure>
    <time_frame>during and after trial medication discontinuation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>complete blood count</measure>
    <time_frame>2 weeks post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>blood chemistry parameters</measure>
    <time_frame>6w post operation</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>urinalysis test</measure>
    <time_frame>2 weeks post operation</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">246</enrollment>
  <condition>Pain</condition>
  <condition>Inflammation</condition>
  <arm_group>
    <arm_group_label>Parecoxib and Celecoxib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients in the study group are supplied sequential treatment with Parecoxib 40 mg intravenously (IV) twice daily (Q12h) for the first 3 days post-surgery followed by Celecoxib 200mg orally twice daily (Q12h) up to 6 weeks post-surgery.&#xD;
Patient-controlled intravenous analgesia (PCIA) with Morphine is administrated to all the subjects starting immediately post-anesthesia and ending at 24h after operation. As long as oral intake is feasible, both the two groups may receive centrally-acting analgesic Tramadol Hydrochloride Sustained release tablets (TRAMCONTIN) as rescue analgesia if VAS score≧3.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Patients in the control group are supplied with the corresponding placebo with the same instructions.&#xD;
Patient-controlled intravenous analgesia (PCIA) with Morphine is administrated to all the subjects starting immediately post-anesthesia and ending at 24h after operation. As long as oral intake is feasible, both the two groups may receive centrally-acting analgesic TRAMCONTIN (Tramadol Hydrochloride Sustained release tablets) as rescue analgesia if VAS score≧3.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Parecoxib and Celecoxib</intervention_name>
    <description>Patients in the study group are supplied sequential treatment with Parecoxib 40 mg intravenously (IV) twice daily (Q12h) for the first 3 days post-surgery followed by Celecoxib 200mg orally twice daily (Q12h) up to 6 weeks post-surgery.</description>
    <arm_group_label>Parecoxib and Celecoxib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>placebo</intervention_name>
    <description>control patients are supplied with the corresponding placebo with the same instructions.</description>
    <arm_group_label>placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. The subject is scheduled to undergo elective unilateral total knee arthroplasty&#xD;
             because of OA, performed under a standardized regimen of general anesthesia, as&#xD;
             specified in this protocol.&#xD;
&#xD;
          2. Evidence of a personally signed and dated informed consent document indicating that&#xD;
             the subject has been informed of all pertinent aspects of the study.&#xD;
&#xD;
          3. The subject is a male or female over 18 years of age.&#xD;
&#xD;
          4. Subjects of childbearing potential must agree to use an effective method of&#xD;
             contraception throughout the study and for 42 days after the last dose of assigned&#xD;
             treatment.&#xD;
&#xD;
          5. Total duration of the surgical procedure is four hours or less.&#xD;
&#xD;
          6. ASA grade 1-3 subjects.&#xD;
&#xD;
          7. Subjects who are willing and able to comply with scheduled visits, treatment plan,&#xD;
             laboratory tests, standardized rehabilitation scheme, and other study procedures.&#xD;
&#xD;
          8. The subject is in satisfactory health as determined by the investigator on the basis&#xD;
             of medical history and physical exam.&#xD;
&#xD;
          9. The subject must demonstrate sufficient psychomotor dexterity and cognitive capacity&#xD;
             to use intravenous (IV) patient-controlled analgesia(PCA).&#xD;
&#xD;
         10. The subject who live near to the hospital may be considered prior for the concern of&#xD;
             convenient and sufficient follow-up.&#xD;
&#xD;
             -&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. The subject requires a revision to previous knee arthroplasty and/or is having a&#xD;
             bilateral knee arthroplasties.&#xD;
&#xD;
          2. The subject requires an emergency knee arthroplasty.&#xD;
&#xD;
          3. Subject uses opioids more than three days/ week prior to operation unless they&#xD;
             discontinue the opioids two months prior to screen.&#xD;
&#xD;
          4. Subject has a known hypersensitivity to COX-2 specific inhibitors, sulfonamides,&#xD;
             lactose, NSAIDs, opioids or acetaminophen/paracetamol.&#xD;
&#xD;
          5. The subject has a history of arthritis:, chronic pain, metastasis, and Paget's&#xD;
             disease.&#xD;
&#xD;
          6. The subject received any investigational medication within 30 days prior to the first&#xD;
             dose of study medication.&#xD;
&#xD;
          7. The subject has any known laboratory abnormality, which in the opinion of the&#xD;
             investigator, would contraindicate study participation ≧1.5 times the upper limit of&#xD;
             the normal reference range.&#xD;
&#xD;
          8. The subject has an active malignancy of any type, or history of a malignancy (Subjects&#xD;
             who have a history of basal cell carcinoma that has been successfully treated can be&#xD;
             entered into the study.&#xD;
&#xD;
          9. Subject had any condition, which could preclude use of NSAIDs or COX-2 specific&#xD;
             inhibitors.&#xD;
&#xD;
         10. The subject has active or suspected esophageal, gastric, pyloric channel, or duodenal&#xD;
             ulceration history.&#xD;
&#xD;
         11. The subject has received warfarin or other anticoagulants during the 30 days preceding&#xD;
             the first dose of study medication.&#xD;
&#xD;
         12. Subject is anticipated to require or requires treatment with lithium.&#xD;
&#xD;
         13. Subject is American Society of Anesthesiologists(ASA) grade 4-5.&#xD;
&#xD;
         14. The subject has a history of a psychiatric disorder requiring new or changing&#xD;
             treatment&#xD;
&#xD;
         15. The subject has a history of uncontrolled chronic disease or a concurrent clinically&#xD;
             significant illness, medical condition.&#xD;
&#xD;
         16. The subject has any cognitive impairment or other characteristics that would in the&#xD;
             investigator's opinion preclude study participation or compliance with protocol&#xD;
             mandated procedures.&#xD;
&#xD;
         17. Subject has a history of asthma or bronchospasm, which requires treatment with&#xD;
             glucocorticoids.&#xD;
&#xD;
         18. Subject had a history of alcohol, analgesic or narcotic abuse.&#xD;
&#xD;
         19. Subject has been previously randomized into the study&#xD;
&#xD;
         20. Subjects who are investigational site staff members or relatives of those site staff&#xD;
&#xD;
         21. Participation in other studies within 3 months before the current study begins and/or&#xD;
             during study participation&#xD;
&#xD;
         22. Other severe acute or chronic medical or psychiatric condition or laboratory&#xD;
             abnormality that may increase the risk associated with study participation.&#xD;
&#xD;
         23. Pregnant females, breastfeeding females, or males and females of childbearing&#xD;
             potential not using effective contraception.&#xD;
&#xD;
             -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Xisheng Weng, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Peking Union Medical College Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Peking Union Medical College Hospital</name>
      <address>
        <city>Beijing</city>
        <zip>100730</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>Carr AJ, Robertsson O, Graves S, Price AJ, Arden NK, Judge A, Beard DJ. Knee replacement. Lancet. 2012 Apr 7;379(9823):1331-40. doi: 10.1016/S0140-6736(11)60752-6. Epub 2012 Mar 6.</citation>
    <PMID>22398175</PMID>
  </reference>
  <reference>
    <citation>Du Q, Ge HJ, Zhu PF. Effects of perioperative analgesia on postoperative inflammatory response. Int J Anesth Resus., 2007, 28(1):48-53.</citation>
  </reference>
  <reference>
    <citation>Holm B, Kristensen MT, Bencke J, Husted H, Kehlet H, Bandholm T. Loss of knee-extension strength is related to knee swelling after total knee arthroplasty. Arch Phys Med Rehabil. 2010 Nov;91(11):1770-6. doi: 10.1016/j.apmr.2010.07.229.</citation>
    <PMID>21044725</PMID>
  </reference>
  <reference>
    <citation>Honsawek S, Deepaisarnsakul B, Tanavalee A, Sakdinakiattikoon M, Ngarmukos S, Preativatanyou K, Bumrungpanichthaworn P. Relationship of serum IL-6, C-reactive protein, erythrocyte sedimentation rate, and knee skin temperature after total knee arthroplasty: a prospective study. Int Orthop. 2011 Jan;35(1):31-5. doi: 10.1007/s00264-010-0973-0. Epub 2010 Feb 21. Erratum In: Int Orthop. 2011 Nov;35(11):1749.</citation>
    <PMID>21203883</PMID>
  </reference>
  <reference>
    <citation>Rasmussen GL, Steckner K, Hogue C, Torri S, Hubbard RC. Intravenous parecoxib sodium foracute pain after orthopedic knee surgery. Am J Orthop (Belle Mead NJ). 2002 Jun;31(6):336-43.</citation>
    <PMID>12083587</PMID>
  </reference>
  <reference>
    <citation>Hubbard RC, Naumann TM, Traylor L, Dhadda S. Parecoxib sodium has opioid-sparing effects in patients undergoing total knee arthroplasty under spinal anaesthesia. Br J Anaesth. 2003 Feb;90(2):166-72. doi: 10.1093/bja/aeg038.</citation>
    <PMID>12538372</PMID>
  </reference>
  <reference>
    <citation>Nussmeier NA, Whelton AA, Brown MT, Joshi GP, Langford RM, Singla NK, Boye ME, Verburg KM. Safety and efficacy of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib after noncardiac surgery. Anesthesiology. 2006 Mar;104(3):518-26. doi: 10.1097/00000542-200603000-00020.</citation>
    <PMID>16508400</PMID>
  </reference>
  <verification_date>April 2019</verification_date>
  <study_first_submitted>July 17, 2013</study_first_submitted>
  <study_first_submitted_qc>July 21, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 24, 2014</study_first_posted>
  <last_update_submitted>April 18, 2019</last_update_submitted>
  <last_update_submitted_qc>April 18, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">April 19, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Peking Union Medical College Hospital</investigator_affiliation>
    <investigator_full_name>Xisheng Weng</investigator_full_name>
    <investigator_title>Department of Orthopedics</investigator_title>
  </responsible_party>
  <keyword>sequential administration</keyword>
  <keyword>pain control</keyword>
  <keyword>inflammation control</keyword>
  <keyword>function recovery</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Osteoarthritis</mesh_term>
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Celecoxib</mesh_term>
    <mesh_term>Parecoxib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02198924
org study id: WI1180091
nct id: NCT02198924
lead sponsor: 
has dmc: Yes
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Total narcotic use
time frame: Post-operative 2 WEEKS
description: The sum of the cumulative Morphine consumption over the first 24 hours postsurgical period and the narcotic drug consumption till 72h, 2w post operation will be converted to morphine equivalents. The converting of tramadol to Morphine equivalents is estimated as 150mg Tramadol equals to 10mg of Morphine injection.
measure: Knee Society Score
time frame: post-operation 6 weeks
description: For more than 20 years, The Knee Society's Knee Scoring System (KSS) has served as a simple, objective way to measure a patient's functional ability before and after total knee arthroplasty (TKA). KSS questionnaire generates three domain scores: KSS function score (walking, stairs and use of knee supports), range of motion and KSS score (pain, range of motion and stability) scores.
measure: Western Ontario and McMaster Universities Arthritis(WOMAC) Index
time frame: prior to operation and at 2w,4w and 6w post operation
description: The WOMAC is a widely used, proprietary set of standardized questionnaires to evaluate the condition of patients with knee osteoarthritis , including pain, stiffness, and physical functioning of the joints. A WOMAC test takes about 12 minutes, and is among the most widely used assessments in arthritis research.
measure: Knee Society Score
time frame: prior to operation and at 2w and 4w post operation
description: For more than 20 years, The Knee Society's Knee Scoring System (KSS) has served as a simple, objective way to measure a patient's functional ability before and after total knee arthroplasty (TKA). KSS questionnaire generates three domain scores: KSS function score (walking, stairs and use of knee supports), range of motion and KSS score (pain, range of motion and stability) scores.
measure: Total Morphine use
time frame: over the first 24 hours postsurgical period
description: The cumulative Morphine consumption over the first 24 hours postsurgical period.
measure: Total narcotic use
time frame: 72h, 4w, 6w post operation
description: The cumulative Morphine consumption and opioid drug over the first 24 hours postsurgical period.
measure: Visual Analogue Scale
time frame: prior to operation and at 24h, 48h, 72h, 2w, 4w and 6w post operation
description: A Visual Analogue Scale (VAS) is a measurement instrument that tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured.
Operationally a VAS is usually a horizontal line, 100 mm in length, anchored by word descriptors at each end. The patient marks on the line the point that they feel represents their perception of their current state. The VAS score is determined by measuring in millimetres from the left hand end of the line to the point that the patient marks.
measure: EuroQol (EQ-5D) Score
time frame: prior to operation and 72h, 2w, 4w and 6w post operation
description: EQ-5D is a standard instrument for use as a measure of health outcome. EQ-5D is primarily designed for self-completion by respondents and is ideally suited for use in postal surveys, in clinics and face-to-face interviews. It is cognitively simple, taking only a few minutes to complete. Instructions to respondents are included in the questionnaire.
measure: Knee circumference
time frame: prior to operation and at 72h, 2w, 4w and 6w post operation
measure: skin temperature
time frame: prior to operation and at 72h, 2w, 4w and 6w post operation
measure: Erythrocyte sedimentation rate(ESR)
time frame: prior to operation and at 72h, 2w, 4w and 6w post operation
measure: C-Reactive Protein，CRP
time frame: prior to operation and at 72h, 2w, 4w and 6w post operation
measure: interleukin-6 concentration in Synovial fluid
time frame: 0h, 24h and 48h post operation
measure: interleukin-8 concentration in Synovial fluid
time frame: 0h, 24h and 48h post operation
measure: interleukin-10 Synovial fluid concentration
time frame: 0h, 24h and 48h post operation
measure: prostaglandin E2 concentration in Synovial fluid
time frame: 0h, 24h and 48h post operation
measure: interleukin-6 concentration in Peripheral blood
time frame: prior to operation and at 72h, 2w, 4w and 6w post operation
measure: interleukin-8 concentration in Peripheral blood
time frame: prior to operation and at 72h, 2w, 4w and 6w post operation
measure: interleukin-10 concentration in Peripheral blood
time frame: prior to operation and at 72h, 2w, 4w and 6w post operation
measure: prostaglandin E2 concentration in Peripheral blood
time frame: prior to operation and at 72h, 2w, 4w and 6w post operation
measure: blood coagulation
time frame: prior to operation and at 72h, 2w, 4w and 6w post operation
measure: The nature, incidence, duration, and severity of adverse events
time frame: until 6w post operation
measure: Discontinuation due to adverse events
time frame: until 6w post operation
measure: Adverse events
time frame: during and after trial medication discontinuation
measure: complete blood count
time frame: 2 weeks post operation
measure: blood chemistry parameters
time frame: 6w post operation
measure: urinalysis test
time frame: 2 weeks post operation
arm group label: Parecoxib and Celecoxib
arm group type: Experimental
description: Patients in the study group are supplied sequential treatment with Parecoxib 40 mg intravenously (IV) twice daily (Q12h) for the first 3 days post-surgery followed by Celecoxib 200mg orally twice daily (Q12h) up to 6 weeks post-surgery.
Patient-controlled intravenous analgesia (PCIA) with Morphine is administrated to all the subjects starting immediately post-anesthesia and ending at 24h after operation. As long as oral intake is feasible, both the two groups may receive centrally-acting analgesic Tramadol Hydrochloride Sustained release tablets (TRAMCONTIN) as rescue analgesia if VAS score≧3.
arm group label: placebo
arm group type: Placebo Comparator
description: Patients in the control group are supplied with the corresponding placebo with the same instructions.
Patient-controlled intravenous analgesia (PCIA) with Morphine is administrated to all the subjects starting immediately post-anesthesia and ending at 24h after operation. As long as oral intake is feasible, both the two groups may receive centrally-acting analgesic TRAMCONTIN (Tramadol Hydrochloride Sustained release tablets) as rescue analgesia if VAS score≧3.
intervention type: Drug
intervention name: Parecoxib and Celecoxib
description: Patients in the study group are supplied sequential treatment with Parecoxib 40 mg intravenously (IV) twice daily (Q12h) for the first 3 days post-surgery followed by Celecoxib 200mg orally twice daily (Q12h) up to 6 weeks post-surgery.
arm group label: Parecoxib and Celecoxib
intervention type: Drug
intervention name: placebo
description: control patients are supplied with the corresponding placebo with the same instructions.
arm group label: placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Xisheng Weng, M.D.
role: Principal Investigator
affiliation: Peking Union Medical College Hospital
facility: 
country: China
citation: Carr AJ, Robertsson O, Graves S, Price AJ, Arden NK, Judge A, Beard DJ. Knee replacement. Lancet. 2012 Apr 7;379(9823):1331-40. doi: 10.1016/S0140-6736(11)60752-6. Epub 2012 Mar 6.
PMID: 22398175
citation: Du Q, Ge HJ, Zhu PF. Effects of perioperative analgesia on postoperative inflammatory response. Int J Anesth Resus., 2007, 28(1):48-53.
citation: Holm B, Kristensen MT, Bencke J, Husted H, Kehlet H, Bandholm T. Loss of knee-extension strength is related to knee swelling after total knee arthroplasty. Arch Phys Med Rehabil. 2010 Nov;91(11):1770-6. doi: 10.1016/j.apmr.2010.07.229.
PMID: 21044725
citation: Honsawek S, Deepaisarnsakul B, Tanavalee A, Sakdinakiattikoon M, Ngarmukos S, Preativatanyou K, Bumrungpanichthaworn P. Relationship of serum IL-6, C-reactive protein, erythrocyte sedimentation rate, and knee skin temperature after total knee arthroplasty: a prospective study. Int Orthop. 2011 Jan;35(1):31-5. doi: 10.1007/s00264-010-0973-0. Epub 2010 Feb 21. Erratum In: Int Orthop. 2011 Nov;35(11):1749.
PMID: 21203883
citation: Rasmussen GL, Steckner K, Hogue C, Torri S, Hubbard RC. Intravenous parecoxib sodium foracute pain after orthopedic knee surgery. Am J Orthop (Belle Mead NJ). 2002 Jun;31(6):336-43.
PMID: 12083587
citation: Hubbard RC, Naumann TM, Traylor L, Dhadda S. Parecoxib sodium has opioid-sparing effects in patients undergoing total knee arthroplasty under spinal anaesthesia. Br J Anaesth. 2003 Feb;90(2):166-72. doi: 10.1093/bja/aeg038.
PMID: 12538372
citation: Nussmeier NA, Whelton AA, Brown MT, Joshi GP, Langford RM, Singla NK, Boye ME, Verburg KM. Safety and efficacy of the cyclooxygenase-2 inhibitors parecoxib and valdecoxib after noncardiac surgery. Anesthesiology. 2006 Mar;104(3):518-26. doi: 10.1097/00000542-200603000-00020.
PMID: 16508400
responsible party type: Principal Investigator
investigator affiliation: Peking Union Medical College Hospital
investigator full name: Xisheng Weng
investigator title: Department of Orthopedics
mesh term: Osteoarthritis
mesh term: Inflammation
mesh term: Celecoxib
mesh term: Parecoxib
sharing ipd: No