<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/NCT04400786</url>
  </required_header>
  <id_info>
    <org_study_id>AROS-MIAS</org_study_id>
    <nct_id>NCT04400786</nct_id>
  </id_info>
  <brief_title>A Randomized Open-labeled Study for Comparing Methods of Using Imrecoxib to Treat AS</brief_title>
  <official_title>A Randomized Open-labeled Study for Comparison of Patient-reported Outcomes Between Two Therapeutic Schedules of Imrecoxib in Ankylosing Spondylitis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Shanghai Zhongshan Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Wu Jieping Medical Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Shanghai Zhongshan Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The selective cox-2 inhibitor has been widely used in the treatment of Ankylosing spondylitis&#xD;
      (AS). The Imrecoxib is a new cox-2 inhibitor. But the treatment strategy has not been decided&#xD;
      yet. To determine which is better in treating AS in the methods between on-demand treatment&#xD;
      and continuous treatment. To solve this question, we designed this study.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Ankylosing spondylitis (AS) is a chronic systemic inflammatory arthritis of unknown etiology,&#xD;
      occurring in young men aged 16-25 and presenting the genetic predisposition. AS is a common&#xD;
      rheumatic disease, with a prevalence of 0.3 ~ 0.5% in general people of China, which means&#xD;
      that about 5 million people in our country suffer from this disease. AS mainly invades the&#xD;
      central axis, characterized by the inflammation of sacroiliitis and attachment points. The&#xD;
      onset of AS is insidious. The early clinical manifestations are mainly inflammatory low back&#xD;
      pain, which gradually affects the lumbar spine, thoracic vertebrae, and cervical vertebrae.&#xD;
      The persistent inflammation will gradually stiffen and fuse the joints, causing osteoporosis&#xD;
      and destruction of the vertebral body, resulting in the ossification of ligaments, and&#xD;
      leading to the disability ultimately. Except for the joint lesions, AS is usually accompanied&#xD;
      by multiple extra-articular manifestations, such as uveal inflammation, psoriasis,&#xD;
      inflammatory bowel disease, etc. Especially, AS is often complicated with multiple&#xD;
      complications symptoms, such as arthritis, arterial disease, fibromyalgia, depression, etc.&#xD;
      In summary, AS has seriously affected the normal work and work of patients, which has become&#xD;
      the main reason for the labor loss in young and middle-aged people. Therefore, it is of great&#xD;
      value for controlling inflammation effectively and alleviate joint pain to improve the life&#xD;
      quality of patients and save social labor.&#xD;
&#xD;
      Non-steroid anti-inflammatory drugs (NSAIDs), the anti-inflammatory and analgesic drugs and&#xD;
      widely used in rheumatic diseases, can effectively relieve pain and quickly improve the&#xD;
      symptoms of inflammatory joint disease. The role of NSAIDs in the treatment of AS is very&#xD;
      important, which could not only generate anti-inflammatory effect, but also improve the joint&#xD;
      function, delay joint erosion, and prevent the formation of osteophyte. The treatment&#xD;
      guidelines of AS in American Rheumatology Association / American Spondyloarthropathy&#xD;
      Collaboration in 2015 recommended continuous prescription NSAIDs as the first-line treatment&#xD;
      for patients with active AS. In the 2016 ASAS / European Guideline of Axial&#xD;
      Spondyloarthropathy, NSAIDs should be treated as the first-line treatment for patients with&#xD;
      joint pain and joint stiffness. Those who respond well to NSAIDs are recommended for&#xD;
      continuous treatment. The latest 2018 APLAR guidelines also recommend that NSAIDs should be&#xD;
      used as first-line treatment for active AS, but the method of continuous treatment or&#xD;
      treatment on demand is not discussed because two clinical trials have shown that the efficacy&#xD;
      of on-demand is not worse than continuous treatment. In summary, NSAIDs are recommended for&#xD;
      the first-line treatment of AS, but the differences in the efficacy, safety, and patient&#xD;
      benefit between continuous treatment and on-demand treatment, as well as the treatment&#xD;
      course, is controversial yet.&#xD;
&#xD;
      NSAIDs could inhibit the activity of cyclooxygenase (COX), blocking the conversion of&#xD;
      arachidonic acid to prostaglandins, prostacyclin, and thromboxane A2. In addition, NSAIDs&#xD;
      could also inhibit the release of bradykinin, inhibit lymphocyte proliferation, and reduce&#xD;
      the migration of granulocyte and macrophages in inflammation. COX includes COX-1 and COX-2.&#xD;
      COX-1 induced prostaglandins mainly generate the physiological and protective effect, such as&#xD;
      maintaining the integrity of the gastrointestinal mucosa, adjusting the renal blood flow, and&#xD;
      guarantee the function of platelets. COX-2 is mainly expressed in macrophages, fibroblasts,&#xD;
      cartilage and endothelial cells with a low level in the basic state. Once stimulated by&#xD;
      cytokines or endothelin, the expression will tremendously increase several times, induce the&#xD;
      production of prostaglandins, and participate in inflammation. NSAIDs could be classified as&#xD;
      non-specific COX inhibitors, selective COX-1 inhibitors, and selective COX-2 inhibitors based&#xD;
      on the effects of different COX. The main adverse reaction of NSAIDs derives from its&#xD;
      inhibitory effect on COX-1, causing adverse gastrointestinal reactions. And the&#xD;
      gastrointestinal ulcers and bleeding are also the most common causes of hospitalization and&#xD;
      death. The selective COX-2 inhibitor is the new generation of NSAIDs, with better&#xD;
      anti-inflammatory and analgesic effects, in that it could specifically inhibit the COX-2 but&#xD;
      has no effect on COX-1, greatly reducing the adverse reaction of gastrointestinal tracts and&#xD;
      kidneys. Multiple clinical trials and meta-analysis have shown that selective COX-2&#xD;
      inhibitors can significantly reduce the gastrointestinal symptoms and peptic ulcer formation&#xD;
      in the endoscopic. Therefore, selective COX-2 owns a much more general application space in&#xD;
      rheumatic diseases.&#xD;
&#xD;
      Most of the COX-2 inhibitors in China are not original research drugs previously, and only&#xD;
      Celecoxib is available in the United States according to FDA. Unearthing new selective cox-2&#xD;
      inhibitor is necessary. Imrecoxib is a COX-2 inhibitor designed by the Chinese Academy of&#xD;
      Medical Sciences and Jiangsu Hengrui Hospital Co., Ltd. in China, which has been approved by&#xD;
      the Chinese Food and Drug Administration (CFDA) for marketing. The recommended dose of&#xD;
      Imrecoxib is 100mg. bid.po. according to the instructions. Studies in vitro has demonstrated&#xD;
      that Imrecoxib could specifically inhibit the COX-2, and inhibit the expression of COX-2 mRNA&#xD;
      to restrain the inflammation. Multiple clinical studies have demonstrated that Imrecoxib was&#xD;
      effective in treating osteoarthritis, with similar efficiency to Celecoxib but without severe&#xD;
      gastrointestinal adverse effect, with a lower percentage of cardiovascular adverse effect,&#xD;
      and with relatively good safety. In 2017, the comparison between Imrecoxib and Celecoxib in&#xD;
      treating serum-negative spondyloarthropathy (SPA) revealed that the effect of Imrecoxib&#xD;
      (10mg.bid.po for 12 weeks) was not worse than that of Celecoxib, which could significantly&#xD;
      alleviate disease activity, joint function and inflammatory markers. But there is a lack of&#xD;
      study with a large sample size and long course to further demonstrate the effectiveness and&#xD;
      safety of Imrecoxib in treating SPA and AS.&#xD;
&#xD;
      The AS disease activity score such as BASDAI and radiological assessment are the main&#xD;
      observation indicators for efficacy evaluation in the clinical study of NSAIDs treating AS&#xD;
      for the moment. But the evaluation of life quality is also important for patients with AS,&#xD;
      which includes 4 respects, the body 's function, disease activity, economic status, and&#xD;
      social status. Data from Taiwan shows that a variety of factors can affect the patient 's&#xD;
      life quality except for the disease activity, including the course of the disease, drinking,&#xD;
      weight, mental, and economic factors, etc. So, adequate life quality assessment and support&#xD;
      should be given to the AS patients. However, there is a lack of studies that employed&#xD;
      patients self-report and patients' life quality assessment as the main observation&#xD;
      indicators. The present study intends to use the results of patients' self-report as the&#xD;
      evaluation criteria, to compare the efficacy and safety between continuous treatment and&#xD;
      on-demand treatment of Imrecoxib for AS under different treatment modes, which could also&#xD;
      provide direct evidence for the optimized applications in rheumatic diseases.&#xD;
&#xD;
      Meanwhile, we also want to find whether on-demand treatment of Imrecoxib could reduce the&#xD;
      occurrence of adverse reactions, reduce the economic burden, and bring more benefits under&#xD;
      the premise that the on-demand treatment is not worse than continuous use of Imrecoxib in&#xD;
      drug efficacy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">May 7, 2020</start_date>
  <completion_date type="Anticipated">June 30, 2022</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2021</primary_completion_date>
  <phase>N/A</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>
    <intervention_model_description>Patients were randomly divided into the continuous treatment group and the on-demand treatment group.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The percent of subjects who achieved moderate improvement in SRM at the 24th week;</measure>
    <time_frame>24 weeks</time_frame>
    <description>The indicator to evaluate the improvement of ASAS HI is the standardized response mean (SRM, SRM = mean / standard deviation the interval of ASAS HI before and after treatment), SRM &lt;0.4 indicates mild improvement, SRM 0.4-0.79 indicates moderate improvement, SRM≥0.8 indicates severe improvement.The percent of patients who achieved moderate improvement in SRM at the 24th week is observed.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The percent of subjects who achieved moderate improvement in SRM at the 12th week.</measure>
    <time_frame>12 weeks.</time_frame>
    <description>The indicator to evaluate the improvement of ASAS HI is the standardized response mean (SRM, SRM = mean / standard deviation the interval of ASAS HI before and after treatment), SRM &lt;0.4 indicates mild improvement, SRM 0.4-0.79 indicates moderate improvement, SRM≥0.8 indicates severe improvement. The percent of patients who achieved moderate improvement in SRM at the 12th week.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The percent of subjects who achieved severe improvement in SRM at the 12th week.</measure>
    <time_frame>12 weeks.</time_frame>
    <description>The indicator to evaluate the improvement of ASAS HI is the standardized response mean (SRM, SRM = mean / standard deviation the interval of ASAS HI before and after treatment), SRM &lt;0.4 indicates mild improvement, SRM 0.4-0.79 indicates moderate improvement, SRM≥0.8 indicates severe improvement. The percent of patients who achieved severe improvement in SRM at the 12th week is evaluated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The percent of subjects who achieved severe improvement in SRM at the 24th week.</measure>
    <time_frame>24 weeks.</time_frame>
    <description>The indicator to evaluate the improvement of ASAS HI is the standardized response mean (SRM, SRM = mean / standard deviation the interval of ASAS HI before and after treatment), SRM &lt;0.4 indicates mild improvement, SRM 0.4-0.79 indicates moderate improvement, SRM≥0.8 indicates severe improvement. The percent of patients who achieved severe improvement in SRM at the 24th week is evaluated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The change of self-evaluation compared with the baseline</measure>
    <time_frame>2, 4, 8, 12, 24 weeks.</time_frame>
    <description>The slef-evaluation is performed with self-evaluation visual simulation method (0~40, higher score indicate more severe condition). The comparison was made between the baseline and the different time point in the follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The change of BASDI compared with the baseline.</measure>
    <time_frame>2, 4, 8, 12, 24 weeks.</time_frame>
    <description>The disease activity was evaluated by the Bath Ankylosing Spondylitis Disease Activity Index (BASDI, 0~70, higher score indicates more severe condition). The comparison was made between the baseline and the different time point in the follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The relation between disease activity assessment and patient self-assessment</measure>
    <time_frame>12, 24 weeks.</time_frame>
    <description>The correlation analysis between disease activity assessment (BASDI) and patient self-evaluation (self-evaluation visual simulation method).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety assessment including adverse effects such as gastrointestinal tract symptoms of two prescription strategy</measure>
    <time_frame>2, 4, 8, 12, 24 weeks.</time_frame>
    <description>The safety assessment indicates the adverse effects or severe adverse effects in the follow-up including disability, prolonged hospitalization, death and so on.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The cost-effectiveness of two prescription strategy</measure>
    <time_frame>24weeks.</time_frame>
    <description>The average cost-effectiveness ratio analysis of two prescription strategy was compared.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">196</enrollment>
  <condition>Ankylosing Spondylitis</condition>
  <condition>Therapeutic Agent Toxicity</condition>
  <arm_group>
    <arm_group_label>On-demand treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This group of 98 ankylosing spondylitis patients is prescribed with intermittent Imrecoxib (100mg.prn.po) according to the feeling of pain till 24 weeks. The sulfasalazine (500mg.tid.po) is used.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Continuous treatment</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>This group of 98 ankylosing spondylitis patients is prescribed with continuous Imrecoxib (100mg.bid.po) for 24 weeks. The sulfasalazine (500mg.tid.po) is used.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>intermittent treatment</intervention_name>
    <description>According to the feeling of pain, the on-demand treatment group is prescribed with or without Imrecoxib (100mg/tablet, 100mg.prn.po), but the maximal dose does not exceed 100 mg per time, twice (morning and evening) per day. The duration lasted for 24 weeks.</description>
    <arm_group_label>On-demand treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>continuous treatment</intervention_name>
    <description>The continuous treatment group is prescribed Imrecoxib (100mg.bid.po) regardless of the pain in the treatment course for 24 weeks.</description>
    <arm_group_label>Continuous treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age 18 ~ 65 (both ends included), regardless of gender;&#xD;
&#xD;
          2. The condition is in the active period, evaluation criteria: Bath Ankylosing&#xD;
             Spondylitis-Disease Activity Index (BASDAI) ≥4 (scale 0-10cm);&#xD;
&#xD;
          3. ESR ≥20mm / h or hsCRP ≥3mg / L;&#xD;
&#xD;
          4. Naive patients who have not received any drugs or physical treatment to treat the AS;&#xD;
             or patients who discontinued all therapeutic drugs for more than 3 months.&#xD;
&#xD;
          5. Female subjects with fertility must agree to take effective contraceptive measures in&#xD;
             the trial.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. complicated with other rheumatic diseases, such as inflammatory bowel disease,&#xD;
             psoriasis, active uveitis, rheumatoid arthritis, systemic lupus erythematosus, primary&#xD;
             Sjogren's syndrome, systemic vasculitis, etc.&#xD;
&#xD;
          2. the anti-infection treatment due to the active periods of acute and chronic infections&#xD;
             such as mycobacterium tuberculosis, hepatitis B, hepatitis C, HIV, etc.&#xD;
&#xD;
          3. complicated with the malignant tumor.&#xD;
&#xD;
          4. complicated with the drug allergies (including sulfonamides, NSAIDs, etc.), allergic&#xD;
             diseases or allergies.&#xD;
&#xD;
          5. Pregnant or lactating women.&#xD;
&#xD;
          6. Abnormal blood system: hemoglobin &lt;80g / L, white blood cells &lt;4.0 × 109 / L, platelet&#xD;
             &lt; 100 × 109 / L.&#xD;
&#xD;
          7. Insufficient liver and kidney function: 1.5 times higher than the upper limit of&#xD;
             normal value of ALT and AST; 1.25 times higher than the upper limit of normal value of&#xD;
             creatinine and urea nitrogen.&#xD;
&#xD;
          8. Insufficient heart function: New York's heart association (NYHA) level ≥ grade II.&#xD;
&#xD;
          9. The usage of analgesic drugs (such as methadone, morphine, etc.) within 4 weeks before&#xD;
             baseline.&#xD;
&#xD;
         10. Patients received the spine or joint surgery within 2 months before of the enrollment.&#xD;
&#xD;
         11. Patients participated the any other clinical trials within 3 months before of the&#xD;
             enrollment.&#xD;
&#xD;
         12. Patients received live vaccination within 3 months before the enrollment.&#xD;
&#xD;
         13. Patients refused to sign the informed consent form, or the patient lack the capacity&#xD;
             to decide for themselves.&#xD;
&#xD;
        Elimination criteria:&#xD;
&#xD;
          1. Violation of the diagnostic criteria for AS.&#xD;
&#xD;
          2. Serious violation of the trial, and the investigators believe that it is not feasible&#xD;
             to exclude subjects who cannot be evaluated for effectiveness.&#xD;
&#xD;
          3. No follow-up records after the enrollment.&#xD;
&#xD;
        Exit criteria&#xD;
&#xD;
          1. The subjects request to stop using the experiment drug in the study.&#xD;
&#xD;
          2. Investigators believe that subjects should be withdrawn due to clinical adverse&#xD;
             events.&#xD;
&#xD;
          3. The subject is pregnant.&#xD;
&#xD;
          4. Serious violation of the study protocol, which affects the effectiveness and safety&#xD;
             evaluation.&#xD;
&#xD;
          5. The subject cannot or does not comply with the requirements of the research project.&#xD;
&#xD;
          6. Subjects who receive any surgical treatment in the study.&#xD;
&#xD;
          7. The investigators believe that further participation in the study is not consistent&#xD;
             with the best interests of the subjects.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Lindi Jiang, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Fudan University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Rongyi Chen, PhD</last_name>
    <phone>02164041990</phone>
    <email>chenry825@hotmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Lili Ma, PhD</last_name>
    <phone>02164041990</phone>
    <email>ma.lili1@zs-hospital.sh.cn</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Lindi Jiang</name>
      <address>
        <city>Shanghai</city>
        <zip>200032</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lindi Jiang</last_name>
      <phone>02164041990</phone>
      <email>zsh-rheum@hotmail.com</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>May 20, 2020</study_first_submitted>
  <study_first_submitted_qc>May 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 26, 2020</study_first_posted>
  <last_update_submitted>May 22, 2020</last_update_submitted>
  <last_update_submitted_qc>May 22, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 27, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Spondylitis</mesh_term>
    <mesh_term>Spondylarthritis</mesh_term>
    <mesh_term>Spondylitis, Ankylosing</mesh_term>
  </condition_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/NCT04400786
org study id: AROS-MIAS
nct id: NCT04400786
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The selective cox-2 inhibitor has been widely used in the treatment of Ankylosing spondylitis
      (AS). The Imrecoxib is a new cox-2 inhibitor. But the treatment strategy has not been decided
      yet. To determine which is better in treating AS in the methods between on-demand treatment
      and continuous treatment. To solve this question, we designed this study.
Ankylosing spondylitis (AS) is a chronic systemic inflammatory arthritis of unknown etiology,
      occurring in young men aged 16-25 and presenting the genetic predisposition. AS is a common
      rheumatic disease, with a prevalence of 0.3 ~ 0.5% in general people of China, which means
      that about 5 million people in our country suffer from this disease. AS mainly invades the
      central axis, characterized by the inflammation of sacroiliitis and attachment points. The
      onset of AS is insidious. The early clinical manifestations are mainly inflammatory low back
      pain, which gradually affects the lumbar spine, thoracic vertebrae, and cervical vertebrae.
      The persistent inflammation will gradually stiffen and fuse the joints, causing osteoporosis
      and destruction of the vertebral body, resulting in the ossification of ligaments, and
      leading to the disability ultimately. Except for the joint lesions, AS is usually accompanied
      by multiple extra-articular manifestations, such as uveal inflammation, psoriasis,
      inflammatory bowel disease, etc. Especially, AS is often complicated with multiple
      complications symptoms, such as arthritis, arterial disease, fibromyalgia, depression, etc.
      In summary, AS has seriously affected the normal work and work of patients, which has become
      the main reason for the labor loss in young and middle-aged people. Therefore, it is of great
      value for controlling inflammation effectively and alleviate joint pain to improve the life
      quality of patients and save social labor.

      Non-steroid anti-inflammatory drugs (NSAIDs), the anti-inflammatory and analgesic drugs and
      widely used in rheumatic diseases, can effectively relieve pain and quickly improve the
      symptoms of inflammatory joint disease. The role of NSAIDs in the treatment of AS is very
      important, which could not only generate anti-inflammatory effect, but also improve the joint
      function, delay joint erosion, and prevent the formation of osteophyte. The treatment
      guidelines of AS in American Rheumatology Association / American Spondyloarthropathy
      Collaboration in 2015 recommended continuous prescription NSAIDs as the first-line treatment
      for patients with active AS. In the 2016 ASAS / European Guideline of Axial
      Spondyloarthropathy, NSAIDs should be treated as the first-line treatment for patients with
      joint pain and joint stiffness. Those who respond well to NSAIDs are recommended for
      continuous treatment. The latest 2018 APLAR guidelines also recommend that NSAIDs should be
      used as first-line treatment for active AS, but the method of continuous treatment or
      treatment on demand is not discussed because two clinical trials have shown that the efficacy
      of on-demand is not worse than continuous treatment. In summary, NSAIDs are recommended for
      the first-line treatment of AS, but the differences in the efficacy, safety, and patient
      benefit between continuous treatment and on-demand treatment, as well as the treatment
      course, is controversial yet.

      NSAIDs could inhibit the activity of cyclooxygenase (COX), blocking the conversion of
      arachidonic acid to prostaglandins, prostacyclin, and thromboxane A2. In addition, NSAIDs
      could also inhibit the release of bradykinin, inhibit lymphocyte proliferation, and reduce
      the migration of granulocyte and macrophages in inflammation. COX includes COX-1 and COX-2.
      COX-1 induced prostaglandins mainly generate the physiological and protective effect, such as
      maintaining the integrity of the gastrointestinal mucosa, adjusting the renal blood flow, and
      guarantee the function of platelets. COX-2 is mainly expressed in macrophages, fibroblasts,
      cartilage and endothelial cells with a low level in the basic state. Once stimulated by
      cytokines or endothelin, the expression will tremendously increase several times, induce the
      production of prostaglandins, and participate in inflammation. NSAIDs could be classified as
      non-specific COX inhibitors, selective COX-1 inhibitors, and selective COX-2 inhibitors based
      on the effects of different COX. The main adverse reaction of NSAIDs derives from its
      inhibitory effect on COX-1, causing adverse gastrointestinal reactions. And the
      gastrointestinal ulcers and bleeding are also the most common causes of hospitalization and
      death. The selective COX-2 inhibitor is the new generation of NSAIDs, with better
      anti-inflammatory and analgesic effects, in that it could specifically inhibit the COX-2 but
      has no effect on COX-1, greatly reducing the adverse reaction of gastrointestinal tracts and
      kidneys. Multiple clinical trials and meta-analysis have shown that selective COX-2
      inhibitors can significantly reduce the gastrointestinal symptoms and peptic ulcer formation
      in the endoscopic. Therefore, selective COX-2 owns a much more general application space in
      rheumatic diseases.

      Most of the COX-2 inhibitors in China are not original research drugs previously, and only
      Celecoxib is available in the United States according to FDA. Unearthing new selective cox-2
      inhibitor is necessary. Imrecoxib is a COX-2 inhibitor designed by the Chinese Academy of
      Medical Sciences and Jiangsu Hengrui Hospital Co., Ltd. in China, which has been approved by
      the Chinese Food and Drug Administration (CFDA) for marketing. The recommended dose of
      Imrecoxib is 100mg. bid.po. according to the instructions. Studies in vitro has demonstrated
      that Imrecoxib could specifically inhibit the COX-2, and inhibit the expression of COX-2 mRNA
      to restrain the inflammation. Multiple clinical studies have demonstrated that Imrecoxib was
      effective in treating osteoarthritis, with similar efficiency to Celecoxib but without severe
      gastrointestinal adverse effect, with a lower percentage of cardiovascular adverse effect,
      and with relatively good safety. In 2017, the comparison between Imrecoxib and Celecoxib in
      treating serum-negative spondyloarthropathy (SPA) revealed that the effect of Imrecoxib
      (10mg.bid.po for 12 weeks) was not worse than that of Celecoxib, which could significantly
      alleviate disease activity, joint function and inflammatory markers. But there is a lack of
      study with a large sample size and long course to further demonstrate the effectiveness and
      safety of Imrecoxib in treating SPA and AS.

      The AS disease activity score such as BASDAI and radiological assessment are the main
      observation indicators for efficacy evaluation in the clinical study of NSAIDs treating AS
      for the moment. But the evaluation of life quality is also important for patients with AS,
      which includes 4 respects, the body 's function, disease activity, economic status, and
      social status. Data from Taiwan shows that a variety of factors can affect the patient 's
      life quality except for the disease activity, including the course of the disease, drinking,
      weight, mental, and economic factors, etc. So, adequate life quality assessment and support
      should be given to the AS patients. However, there is a lack of studies that employed
      patients self-report and patients' life quality assessment as the main observation
      indicators. The present study intends to use the results of patients' self-report as the
      evaluation criteria, to compare the efficacy and safety between continuous treatment and
      on-demand treatment of Imrecoxib for AS under different treatment modes, which could also
      provide direct evidence for the optimized applications in rheumatic diseases.

      Meanwhile, we also want to find whether on-demand treatment of Imrecoxib could reduce the
      occurrence of adverse reactions, reduce the economic burden, and bring more benefits under
      the premise that the on-demand treatment is not worse than continuous use of Imrecoxib in
      drug efficacy.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Patients were randomly divided into the continuous treatment group and the on-demand treatment group.
primary purpose: Treatment
masking: None (Open Label)
measure: The percent of subjects who achieved moderate improvement in SRM at the 24th week;
time frame: 24 weeks
description: The indicator to evaluate the improvement of ASAS HI is the standardized response mean (SRM, SRM = mean / standard deviation the interval of ASAS HI before and after treatment), SRM <0.4 indicates mild improvement, SRM 0.4-0.79 indicates moderate improvement, SRM≥0.8 indicates severe improvement.The percent of patients who achieved moderate improvement in SRM at the 24th week is observed.
measure: The percent of subjects who achieved moderate improvement in SRM at the 12th week.
time frame: 12 weeks.
description: The indicator to evaluate the improvement of ASAS HI is the standardized response mean (SRM, SRM = mean / standard deviation the interval of ASAS HI before and after treatment), SRM <0.4 indicates mild improvement, SRM 0.4-0.79 indicates moderate improvement, SRM≥0.8 indicates severe improvement. The percent of patients who achieved moderate improvement in SRM at the 12th week.
measure: The percent of subjects who achieved severe improvement in SRM at the 12th week.
time frame: 12 weeks.
description: The indicator to evaluate the improvement of ASAS HI is the standardized response mean (SRM, SRM = mean / standard deviation the interval of ASAS HI before and after treatment), SRM <0.4 indicates mild improvement, SRM 0.4-0.79 indicates moderate improvement, SRM≥0.8 indicates severe improvement. The percent of patients who achieved severe improvement in SRM at the 12th week is evaluated.
measure: The percent of subjects who achieved severe improvement in SRM at the 24th week.
time frame: 24 weeks.
description: The indicator to evaluate the improvement of ASAS HI is the standardized response mean (SRM, SRM = mean / standard deviation the interval of ASAS HI before and after treatment), SRM <0.4 indicates mild improvement, SRM 0.4-0.79 indicates moderate improvement, SRM≥0.8 indicates severe improvement. The percent of patients who achieved severe improvement in SRM at the 24th week is evaluated.
measure: The change of self-evaluation compared with the baseline
time frame: 2, 4, 8, 12, 24 weeks.
description: The slef-evaluation is performed with self-evaluation visual simulation method (0~40, higher score indicate more severe condition). The comparison was made between the baseline and the different time point in the follow-up.
measure: The change of BASDI compared with the baseline.
time frame: 2, 4, 8, 12, 24 weeks.
description: The disease activity was evaluated by the Bath Ankylosing Spondylitis Disease Activity Index (BASDI, 0~70, higher score indicates more severe condition). The comparison was made between the baseline and the different time point in the follow-up.
measure: The relation between disease activity assessment and patient self-assessment
time frame: 12, 24 weeks.
description: The correlation analysis between disease activity assessment (BASDI) and patient self-evaluation (self-evaluation visual simulation method).
measure: Safety assessment including adverse effects such as gastrointestinal tract symptoms of two prescription strategy
time frame: 2, 4, 8, 12, 24 weeks.
description: The safety assessment indicates the adverse effects or severe adverse effects in the follow-up including disability, prolonged hospitalization, death and so on.
measure: The cost-effectiveness of two prescription strategy
time frame: 24weeks.
description: The average cost-effectiveness ratio analysis of two prescription strategy was compared.
arm group label: On-demand treatment
arm group type: Experimental
description: This group of 98 ankylosing spondylitis patients is prescribed with intermittent Imrecoxib (100mg.prn.po) according to the feeling of pain till 24 weeks. The sulfasalazine (500mg.tid.po) is used.
arm group label: Continuous treatment
arm group type: Active Comparator
description: This group of 98 ankylosing spondylitis patients is prescribed with continuous Imrecoxib (100mg.bid.po) for 24 weeks. The sulfasalazine (500mg.tid.po) is used.
intervention type: Procedure
intervention name: intermittent treatment
description: According to the feeling of pain, the on-demand treatment group is prescribed with or without Imrecoxib (100mg/tablet, 100mg.prn.po), but the maximal dose does not exceed 100 mg per time, twice (morning and evening) per day. The duration lasted for 24 weeks.
arm group label: On-demand treatment
intervention type: Procedure
intervention name: continuous treatment
description: The continuous treatment group is prescribed Imrecoxib (100mg.bid.po) regardless of the pain in the treatment course for 24 weeks.
arm group label: Continuous treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Lindi Jiang, PhD
role: Study Chair
affiliation: Fudan University
last name: Rongyi Chen, PhD
phone: 02164041990
email: chenry825@hotmail.com
last name: Lili Ma, PhD
phone: 02164041990
email: ma.lili1@zs-hospital.sh.cn
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Sponsor
mesh term: Spondylitis
mesh term: Spondylarthritis
mesh term: Spondylitis, Ankylosing
sharing ipd: No