xml: <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/NCT06020144</url>
    </required_header>
    <id_info>
      <org_study_id>TLL-018-301</org_study_id>
      <nct_id>NCT06020144</nct_id>
    </id_info>
    <brief_title>A Phase 3 Study Comparing TLL-018 to Tofacitinib in RA Subjects With Inadequate Response or Intolerance to bDMARDs</brief_title>
    <acronym>TARA</acronym>
    <official_title>A Phase 3, Randomized, Double-Blind, Positive-controlled, Head-to-Head Monotherapy Study Comparing TLL-018 to Tofacitinib in Subjects With Active Rheumatoid Arthritis With Inadequate Response or Intolerance to Biologic DMARDs (bDMARDs)</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Hangzhou Highlightll Pharmaceutical Co., Ltd</agency>
        <agency_class>Industry</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Hangzhou Highlightll Pharmaceutical Co., Ltd</source>
    <oversight_info>
      <has_dmc>No</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>
        A randomized, double-blind, double-dummy, positive-controlled, phase 3 study to assess the&#xD;
        safety and efficacy of TLL-018 in active rheumatoid arthritis subjects who had an inadequate&#xD;
        response or intolerance to Biologic DMARDs.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        This is a randomized, double-blind, double-dummy, tofacitinib-parallel-group, phase 3 study&#xD;
        to assess the safety and efficacy of TLL-018 in active rheumatoid arthritis subjects who had&#xD;
        an inadequate response or intolerance to Biologic DMARDs.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">September 30, 2023</start_date>
    <completion_date type="Anticipated">September 30, 2025</completion_date>
    <primary_completion_date type="Anticipated">February 28, 2025</primary_completion_date>
    <phase>Phase 3</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>Triple (Participant, Care Provider, Investigator)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Proportion of subjects achieving American College of Rheumatology 50% (ACR50) Response</measure>
      <time_frame>Week 24</time_frame>
      <description>ACR50 response: greater than or equal to (&gt;=) 50 percent (%) improvement in painful and tender joint count; &gt;= 50% improvement in swollen joint count; and &gt;= 50% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP)at each visit.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Proportion of subjects achieving DAS28-hsCRP &lt;2.6</measure>
      <time_frame>Week 24</time_frame>
      <description>Disease Activity Score (DAS) based on a 28 joint count hsCRP consisted of composite numerical score of following variables: tender joint count (TJC28), swollen joint count (SJC28), hsCRP (mg/mL), and patient's global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP equals to (=) 0.56*square root (sqrt) (TJC28) plus (+) 0.28*sqrt (SJC28) + 0.36*natural log(hsCRP+1) + 0.014*participant's global assessment of disease activity + 0.96. Scores ranged 0-9.4, where lower scores indicated less disease activity.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Proportion of subjects achieving American College of Rheumatology 20% (ACR20) and 70% (ACR70) Response</measure>
      <time_frame>Week 24</time_frame>
      <description>ACR20/70 response: greater than or equal to (&gt;=) 20/70 percent (%) improvement in painful and tender joint count; &gt;= 20%/70% improvement in swollen joint count; and &gt;= 20%/70% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP)at each visit.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change From Baseline in Disease Activity Score Based on 28-Joints Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP)</measure>
      <time_frame>Week 24</time_frame>
      <description>Disease Activity Score (DAS) based on a 28 joint count hsCRP consisted of composite numerical score of following variables: tender joint count (TJC28), swollen joint count (SJC28), hsCRP (mg/mL), and patient's global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP equals to (=) 0.56*square root (sqrt) (TJC28) plus (+) 0.28*sqrt (SJC28) + 0.36*natural log(hsCRP+1) + 0.014*participant's global assessment of disease activity + 0.96. Scores ranged 0-9.4, where lower scores indicated less disease activity. Change = value at observation minus value at baseline.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score</measure>
      <time_frame>Week 24</time_frame>
      <description>HAQ-DI score was an evaluation of the functional status for a participant. The 20-question instrument assessed the degree of difficulty a person had in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area were scored from 0, indicated no difficulty, to 3, indicated inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range: 0-3 where 0 = least difficulty and 3 = extreme difficulty.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Changes From Baseline in SF-36 Score</measure>
      <time_frame>Week 24</time_frame>
      <description>SF-36 score was an evaluation of the functional status for a participant,taping eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Coded numeric values are recoded per the scoring key. All items are scored so that a high score defines a more favorable health state. Each item is scored on a o to 100 range. Items in the same scale are averaged together to create the 8 scale scores.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Proportion of subjects achieving DAS28-hsCRP &lt;＝3.2</measure>
      <time_frame>Week 24</time_frame>
      <description>Disease Activity Score (DAS) based on a 28 joint count hsCRP consisted of composite numerical score of following variables: tender joint count (TJC28), swollen joint count (SJC28), hsCRP (mg/mL), and patient's global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP equals to (=) 0.56*square root (sqrt) (TJC28) plus (+) 0.28*sqrt (SJC28) + 0.36*natural log(hsCRP+1) + 0.014*participant's global assessment of disease activity + 0.96. Scores ranged 0-9.4, where lower scores indicated less disease activity.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Proportion of subjects achieving CDAI &lt;＝10</measure>
      <time_frame>Week 24</time_frame>
      <description>Clinical Disease Activity Index equals the sum of score of following variables：Tender joint count (TJC28), Swollen joint count (SJC28), Patient's Global Assessment of Arthritis, Physician's Global Assessment of Arthritis</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">450</enrollment>
    <condition>Rheumatoid Arthritis</condition>
    <arm_group>
      <arm_group_label>sequence A</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>TLL018 tablets, 2piece,BID</description>
    </arm_group>
    <arm_group>
      <arm_group_label>sequence B</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Tofacitinib tablets, 1piece,BID</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>TLL-018</intervention_name>
      <description>Oral tablets administered 2pieces BID for 52 weeks.</description>
      <arm_group_label>sequence A</arm_group_label>
      <other_name>TLL-018 tablets</other_name>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Tofacitinib</intervention_name>
      <description>Oral tablets administered 1pieces BID for 52 weeks.</description>
      <arm_group_label>sequence B</arm_group_label>
      <other_name>Tofacitinib tablets</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Aged between 18 and 65;&#xD;
  &#xD;
            -  Meet the diagnostic criteria of rheumatoid arthritis of the American College of&#xD;
               Rheumatology/European Alliance against Rheumatism (ACR/EULAR,2010) with duration of at&#xD;
               least 3 months;&#xD;
  &#xD;
            -  Meet the criteria for active rheumatoid arthritis；&#xD;
  &#xD;
            -  Have received at least one kind of bDMARDs for three months or longer and show&#xD;
               inadequate response or intolerance to at least one kind of bDMARDs；&#xD;
  &#xD;
            -  Meet the ACR (1991) grading criteria of grade I, II or III；&#xD;
  &#xD;
            -  Discontinuation of bDMARDs or JAK inhibitors for more than four weeks；&#xD;
  &#xD;
            -  To sustain a stable status, oral administration of stable doses of glucocorticoids (≤&#xD;
               prednisone 10 mg/day or equivalent corticosteroids) and stable doses of nonsteroidal&#xD;
               anti-inflammatory drugs (NSAIDs) are allowed to use, provided that stable doses are&#xD;
               maintained for at least one week prior to the study；&#xD;
  &#xD;
            -  BMI index is less than 35 kg/m2;&#xD;
  &#xD;
            -  Women of Child Bearing Potential (WOCBP) should not be pregnant or breastfeeding and&#xD;
               the pregnancy test should be negative before randomization;&#xD;
  &#xD;
            -  Subjects (whether male or female) should have adequate barrier contraception during&#xD;
               the whole treatment period and at least 90 days after treatment; subjects should avoid&#xD;
               the sperm or ovum donation for at least six months after treatment；&#xD;
  &#xD;
            -  Subjects understand the informed consent form (ICF), volunteer for the study and sign&#xD;
               the ICF;&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  With other rheumatic diseases;&#xD;
  &#xD;
            -  With other systemic inflammatory diseases;&#xD;
  &#xD;
            -  With progressive or uncontrolled symptoms of renal, hepatic, hematologic,&#xD;
               gastrointestinal, endocrine, pulmonary, cardiovascular, neurologic, psychiatric, or&#xD;
               cerebral disease;&#xD;
  &#xD;
            -  Previous history of severe hematologic diseases;&#xD;
  &#xD;
            -  Previous history of malignancy within five years, with exception of cured basal cell&#xD;
               carcinoma or cutaneous squamous cell carcinoma or cervical carcinoma in situ.&#xD;
  &#xD;
            -  With active infection before randomization;&#xD;
  &#xD;
            -  Herpes zoster occurred within 1 year prior to randomization; disseminated or recurrent&#xD;
               herpes zoster prior to randomization; disseminated herpes simplex before&#xD;
               randomization;&#xD;
  &#xD;
            -  Previous history of active tuberculosis (TB) and no evidence of clinical cure or&#xD;
               imaging evidence of active TB; or T-spot or PPD positive at screening but have&#xD;
               received TB preventive therapy less than one month;&#xD;
  &#xD;
            -  HBsAg positive (or HBsAg negative but anti-HBc positive and HBV-DNA quantitative test&#xD;
               positive), HCV antibody and HCV-RNA positive, or HIV antibody positive;&#xD;
  &#xD;
            -  Previous history of thrombocytopenia, coagulopathy, or platelet dysfunction;&#xD;
  &#xD;
            -  Previous history of cardiovascular and cerebrovascular accidents;&#xD;
  &#xD;
            -  Previous history of thromboembolism or risk factors;&#xD;
  &#xD;
            -  Previous history of gastrointestinal perforation;&#xD;
  &#xD;
            -  Temporary usage of NSAIDs within 24 hours prior to the baseline visit;&#xD;
  &#xD;
            -  Have received anti-rheumatic herb within 4 weeks before randomization;&#xD;
  &#xD;
            -  Have received interferon therapy within 4 weeks before randomization;&#xD;
  &#xD;
            -  Have donated blood more than 400 ml or received blood transfusion within 3 months&#xD;
               prior to the study;&#xD;
  &#xD;
            -  Have received any live vaccine within 2 months before randomization or plan to receive&#xD;
               a live vaccine during the study;&#xD;
  &#xD;
            -  Have experienced major surgery within 4 weeks before randomization, or expected to&#xD;
               receive major surgical treatment after enrollment;&#xD;
  &#xD;
            -  Laboratory test results are abnormal and may interfere the study judged by&#xD;
               investigators;&#xD;
  &#xD;
            -  Use of potent opioids within 4 weeks before the baseline visit;&#xD;
  &#xD;
            -  Allergy to ingredients or excipients of tofacitinib or TLL-018;&#xD;
  &#xD;
            -  Unable to accomplish evaluation in study;&#xD;
  &#xD;
            -  Receiving any study drug within 4 weeks or less than 5 elimination of half-life&#xD;
               period) before randomization (whichever is longer);&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>65 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <location>
      <facility>
        <name>Peking Union Medical College Hospital</name>
        <address>
          <city>Beijing</city>
          <state>Beijing</state>
          <country>China</country>
        </address>
      </facility>
      <contact>
        <last_name>Guang Yang</last_name>
        <phone>+86-571-88753285</phone>
        <email>guang.yang@tllpharma.com</email>
      </contact>
      <contact_backup>
        <last_name>Xiaofeng Zeng, MD</last_name>
      </contact_backup>
    </location>
    <location_countries>
      <country>China</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 25, 2023</study_first_submitted>
    <study_first_submitted_qc>August 25, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 31, 2023</study_first_posted>
    <last_update_submitted>August 25, 2023</last_update_submitted>
    <last_update_submitted_qc>August 25, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 31, 2023</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>Arthritis</mesh_term>
      <mesh_term>Arthritis, Rheumatoid</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Tofacitinib</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT06020144
  org study id: TLL-018-301
  nct id: NCT06020144
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  A randomized, double-blind, double-dummy, positive-controlled, phase 3 study to assess the
        safety and efficacy of TLL-018 in active rheumatoid arthritis subjects who had an inadequate
        response or intolerance to Biologic DMARDs.
  This is a randomized, double-blind, double-dummy, tofacitinib-parallel-group, phase 3 study
        to assess the safety and efficacy of TLL-018 in active rheumatoid arthritis subjects who had
        an inadequate response or intolerance to Biologic DMARDs.
  allocation: Randomized
  intervention model: Parallel Assignment
  primary purpose: Treatment
  masking: Triple (Participant, Care Provider, Investigator)
  measure: Proportion of subjects achieving American College of Rheumatology 50% (ACR50) Response
  time frame: Week 24
  description: ACR50 response: greater than or equal to (>=) 50 percent (%) improvement in painful and tender joint count; >= 50% improvement in swollen joint count; and >= 50% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP)at each visit.
  measure: Proportion of subjects achieving DAS28-hsCRP <2.6
  time frame: Week 24
  description: Disease Activity Score (DAS) based on a 28 joint count hsCRP consisted of composite numerical score of following variables: tender joint count (TJC28), swollen joint count (SJC28), hsCRP (mg/mL), and patient's global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP equals to (=) 0.56*square root (sqrt) (TJC28) plus (+) 0.28*sqrt (SJC28) + 0.36*natural log(hsCRP+1) + 0.014*participant's global assessment of disease activity + 0.96. Scores ranged 0-9.4, where lower scores indicated less disease activity.
  measure: Proportion of subjects achieving American College of Rheumatology 20% (ACR20) and 70% (ACR70) Response
  time frame: Week 24
  description: ACR20/70 response: greater than or equal to (>=) 20/70 percent (%) improvement in painful and tender joint count; >= 20%/70% improvement in swollen joint count; and >= 20%/70% improvement in at least 3 of 5 remaining ACR core measures: patient assessment of pain; patient global assessment of disease activity; physician global assessment of disease activity; self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ]); and C-Reactive Protein (CRP)at each visit.
  measure: Change From Baseline in Disease Activity Score Based on 28-Joints Count-High-Sensitivity C-reactive Protein (DAS28-hsCRP)
  time frame: Week 24
  description: Disease Activity Score (DAS) based on a 28 joint count hsCRP consisted of composite numerical score of following variables: tender joint count (TJC28), swollen joint count (SJC28), hsCRP (mg/mL), and patient's global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP equals to (=) 0.56*square root (sqrt) (TJC28) plus (+) 0.28*sqrt (SJC28) + 0.36*natural log(hsCRP+1) + 0.014*participant's global assessment of disease activity + 0.96. Scores ranged 0-9.4, where lower scores indicated less disease activity. Change = value at observation minus value at baseline.
  measure: Changes From Baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) Total Score
  time frame: Week 24
  description: HAQ-DI score was an evaluation of the functional status for a participant. The 20-question instrument assessed the degree of difficulty a person had in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and activities of daily living). Responses in each functional area were scored from 0, indicated no difficulty, to 3, indicated inability to perform a task in that area. Overall score was computed as the sum of domain scores and divided by the number of domains answered. Total possible score range: 0-3 where 0 = least difficulty and 3 = extreme difficulty.
  measure: Changes From Baseline in SF-36 Score
  time frame: Week 24
  description: SF-36 score was an evaluation of the functional status for a participant,taping eight health concepts: physical functioning, bodily pain, role limitations due to physical health problems, role limitations due to personal or emotional problems, emotional well-being, social functioning, energy/fatigue, and general health perceptions. Coded numeric values are recoded per the scoring key. All items are scored so that a high score defines a more favorable health state. Each item is scored on a o to 100 range. Items in the same scale are averaged together to create the 8 scale scores.
  measure: Proportion of subjects achieving DAS28-hsCRP <＝3.2
  time frame: Week 24
  description: Disease Activity Score (DAS) based on a 28 joint count hsCRP consisted of composite numerical score of following variables: tender joint count (TJC28), swollen joint count (SJC28), hsCRP (mg/mL), and patient's global assessment of disease activity. DAS28-hsCRP was calculated using following formula: DAS28-hsCRP equals to (=) 0.56*square root (sqrt) (TJC28) plus (+) 0.28*sqrt (SJC28) + 0.36*natural log(hsCRP+1) + 0.014*participant's global assessment of disease activity + 0.96. Scores ranged 0-9.4, where lower scores indicated less disease activity.
  measure: Proportion of subjects achieving CDAI <＝10
  time frame: Week 24
  description: Clinical Disease Activity Index equals the sum of score of following variables：Tender joint count (TJC28), Swollen joint count (SJC28), Patient's Global Assessment of Arthritis, Physician's Global Assessment of Arthritis
  arm group label: sequence A
  arm group type: Experimental
  description: TLL018 tablets, 2piece,BID
  arm group label: sequence B
  arm group type: Active Comparator
  description: Tofacitinib tablets, 1piece,BID
  intervention type: Drug
  intervention name: TLL-018
  description: Oral tablets administered 2pieces BID for 52 weeks.
  arm group label: sequence A
  other name: TLL-018 tablets
  intervention type: Drug
  intervention name: Tofacitinib
  description: Oral tablets administered 1pieces BID for 52 weeks.
  arm group label: sequence B
  other name: Tofacitinib tablets
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 65 Years
  healthy volunteers: No
  facility: 
  contact: 
  contact backup: 
  country: China
  responsible party type: Sponsor
  mesh term: Arthritis
  mesh term: Arthritis, Rheumatoid
  mesh term: Tofacitinib
  sharing ipd: No