TLL-018 in Patients With Moderate to Severe Active Rheumatoid Arthritis With Inadequate Response or Intolerance to csDMARDs
A Randomized, Double-Blind, Placebo-Controlled Parallel-Group Phase II Study to Evaluate the Efficacy and Safety of TLL-018 in Patients With Moderate to Severe Active Rheumatoid Arthritis With Inadequate Response or Intolerance to csDMARDs
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
The study will consist of a 35-day screening period, a 12-week randomized, double-blind, parallel-group, placebo-controlled treatment period (Period 1: primary efficacy observation period), a 12-week open-label treatment period with TLL-018 (Period 2: extension observation period), and a 14-day safety follow-up period.
Approximately 90 study participants will be randomized at a 2:1 ratio to the TLL-018 20 mg group (treatment group, 60 participants, administered twice daily [BID]) or the placebo group (placebo group, 30 participants, administered twice daily [BID]).
Treatment group: TLL-018 20 mg BID in Period 1 → TLL-018 20 mg BID in Period 2 Placebo group: Placebo BID in Period 1 → TLL-018 20 mg BID in Period 2
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Beijing Municipality
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Beijing, Beijing Municipality, China
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
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Contact:
- Zeng Xiaofeng Zeng, PhD
- Phone Number: +8613501069845
- Email: Xiaofeng.zeng@cstar.org.cn
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Contact:
- Zhang Li Zhang, PhD
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
1 Aged 18 to 70 years inclusive, any sex; body mass index [BMI = weight (kg)/height² (m²)] ≤ 35 kg/m².
2 "Meets the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria for active rheumatoid arthritis (RA), with a disease duration of at least 3 months at the screening visit： Has received conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) for ≥ 3 months prior to screening, with a stable dose for at least 4 weeks before randomization； Active rheumatoid arthritis meeting all of the following criteria: ≥6 swollen joints (SJC, 66-joint count) and ≥6 tender joints (TJC, 68-joint count) at screening and baseline visits. Joints that have undergone major surgery or received intra-articular injection within 4 weeks before randomization will be excluded from SJC and TJC counts. High-sensitivity C-reactive protein (hsCRP) > upper limit of normal (ULN) or ≥5 mg/L at baseline (CRP testing is acceptable; hsCRP is preferred)." 3 Functional Class I, II, or III according to the 1991 American College of Rheumatology (ACR) rheumatoid arthritis functional classification criteria.
4 "Organ function must satisfy the following laboratory criteria: Bone marrow: hemoglobin ≥90 g/L; platelets ≥100 ×10⁹/L; absolute neutrophil count ≥1.5 ×10⁹/L; lymphocyte count ≥0.8 ×10⁹/L; white blood cell count ≥2.5 ×10⁹/L.
Hepatic function: total bilirubin ≤1.5 × ULN; aspartate aminotransferase (AST) OR alanine aminotransferase (ALT) ≤1.5 × ULN.
Renal function: serum creatinine <1.2 × ULN. Urinalysis: urine protein ≤1+. If urine protein >1+, a 24-hour urine protein collection is required, with total urinary protein ≤1 g." 5 Women of childbearing potential (WOCBP) must not be pregnant or breastfeeding. A pregnancy test (e.g., β-HCG assay) must be performed prior to study entry (last menstrual period will be documented). All participants and their partners must agree to use effective contraception (as judged by the Investigator) from the first dose of investigational product until at least 90 days after the last dose (see Appendix 12). Participants must have no plans to donate sperm or ova from screening through at least 6 months after the last study drug administration.
6 The participant understands the informed consent form, voluntarily agrees to participate in the study, and provides written informed consent. Informed consent must be obtained prior to performance of any study-related procedures.
Exclusion Criteria:
1 Evidence or diagnosis of other rheumatic diseases prior to screening (secondary Sjögren's syndrome excluded), including systemic lupus erythematosus, psoriatic arthritis, mixed connective tissue disease, primary Sjögren's syndrome, dermatomyositis, polymyositis, systemic sclerosis, and ankylosing spondylitis.
2 Presence of active fibromyalgia that, in the Investigator's judgment, may interfere with the evaluation of rheumatoid arthritis disease activity.
3 Prior diagnosis of other systemic inflammatory diseases, including but not limited to juvenile chronic arthritis, inflammatory bowel disease, active vasculitis (excluding venous rheumatoid nodules), spondyloarthropathy, and psoriatic arthritis.
4 Diagnosis of Felty's syndrome (rheumatoid arthritis with splenomegaly). 5 Presence of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, cardiovascular, neurological, psychiatric, or cerebral diseases that, in the Investigator's opinion, would place the participant at unacceptable risk.
6 A history of lymphoproliferative disorders (including but not limited to EBV-associated lymphoproliferative diseases, lymphoma, and leukemia), or presence of any current signs or symptoms suggestive of active lymphoproliferative disease.
7 A previous history of severe hematological diseases such as aplastic anemia and myelodysplastic syndrome, or any disease condition that may cause hemolysis or erythrocyte instability, including malaria and hemolytic anemia.
8 Current or previous history of thrombocytopenia, coagulation disorders, or platelet function disorders.
9 History of cardiovascular or cerebrovascular events or surgeries within 12 months prior to screening, including but not limited to myocardial infarction, unstable angina, acute coronary syndrome, cerebral hemorrhage, cerebral infarction, coronary stent implantation, percutaneous transluminal coronary angioplasty, and coronary artery bypass grafting.
10 History of thromboembolic events within 12 months prior to screening (e.g., pulmonary thromboembolism, deep vein thrombosis, mesenteric arterial embolism), or presence of current high thromboembolic risk factors, such as immobilization within 12 weeks before screening, congenital or hereditary thrombophilia, or antiphospholipid antibody syndrome.
11 History of gastrointestinal perforation prior to screening (perforation caused by appendicitis or trauma is excluded).
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Double
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
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Experimental: TLL-018 20mg
TLL-018 20 mg, administered orally twice daily (BID) for 12 weeks during the double-blind treatment period.
Eligible participants completing the double-blind phase may continue to receive TLL-018 in the subsequent 12-week open-label extension period.
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Treatment group: TLL-018 20 mg BID in Period 1 → TLL-018 20 mg BID in Period 2
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Placebo Comparator: Placebo
Matching placebo for TLL-018, administered orally twice daily (BID) for 12 weeks during the double-blind treatment period.
Eligible participants completing the double-blind phase may transition to receive TLL-018 in the subsequent 12-week open-label extension period.
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Placebo group: Placebo BID in Period 1 → TLL-018 20 mg BID in Period 2
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12
Time Frame: Week 12
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Participants who met all of the following 3 conditions for improvement from baseline were classified as achieving the ACR20 response criteria:
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Week 12
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Percentage of Participants With an American College of Rheumatology 20/50/70% (ACR20/50/70) Response
Time Frame: Week 2 to Week 24 (ACR20, excluding Week 12)
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Participants who met all of the following 3 conditions for improvement from baseline were classified as achieving the ACR20/50/70 response criteria:
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Week 2 to Week 24 (ACR20, excluding Week 12)
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Change From Baseline in Disease Activity Score 28 (DAS28) (hsCRP)
Time Frame: Baseline to Week 24
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The DAS28 is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100), and hsCRP (in mg/L).
Scores on the DAS28 range from 0 to approximately 10, where higher scores indicate more disease activity.
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Baseline to Week 24
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Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(hsCRP)
Time Frame: Week 2 to Week 24
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Low disease activity based on DAS28 (hsCRP) is defined a DAS28 (hsCRP) score of ≤ 3.2.
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Week 2 to Week 24
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Percentage of Participants Achieving Clinical Remission Based on DAS28 (hsCRP)
Time Frame: Week 2 to Week 24
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Clinical remission (CR) based on DAS28 (hsCRP) is defined as achieving a DAS28 (hsCRP) score of less than 2.6.
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Week 2 to Week 24
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Change From Baseline in CDAI Scores
Time Frame: Baseline to Week 24
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Change from baseline in Clinical Disease Activity Index (CDAI) at scheduled assessment time points. CDAI = tender joint count (68 joints) + swollen joint count (66 joints) + Physician's Global Assessment + Patient's Global Assessment. |
Baseline to Week 24
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Change From Baseline in SDAI Scores
Time Frame: Baseline to Week 24
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Change from baseline in Simplified Disease Activity Index (SDAI) at scheduled assessment time points. SDAI = CDAI + high-sensitivity C-reactive protein (hsCRP). |
Baseline to Week 24
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Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI)
Time Frame: Baseline to Week 24
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he Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire that measures the degree of difficulty a person has in accomplishing tasks in 8 functional areas (dressing, arising, eating, walking, hygiene, reaching, gripping, and errands and chores) over the past week. Participants assessed their ability to do each task on a scale from 0 (without any difficulty) to 3 (unable to do). Scores were averaged to provide an overall score ranging from 0 to 3, where 0 represents no disability and 3 represents very severe, high-dependency disability. A negative change from Baseline in the overall score indicates improvement. |
Baseline to Week 24
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Change From Baseline in Duration of Morning Stiffness
Time Frame: Baseline to Week 24
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Participants were asked to indicate the time it took for them to get as limber as possible after awakening with morning stiffness over the past 7 days.
A negative change from Baseline indicates improvement.
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Baseline to Week 24
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Change From Baseline in Patient's Assessment of Pain
Time Frame: Baseline to Week 24
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Participants were asked to indicate the severity of their arthritis pain within the previous week on a visual analog scale (VAS) from 0 to 10.
A score of 0 indicates "no pain" and a score of 10 indicates "worst possible pain."
A negative change from Baseline indicates improvement.
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Baseline to Week 24
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Change From Baseline in Patient's Global Assessment of Disease Activity (PtGA)
Time Frame: Baseline to Week 24
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Participants rated their disease activity for the past 24 hours using a Patient's Global Assessment of Disease Activity Global visual analogue scale (VAS).
The range is 0 to 10 cm, with 0 representing no disease activity and 10 representing severe disease activity.
Negative values indicate improvement from baseline.
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Baseline to Week 24
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Change From Baseline in Physician's Global Assessment of Disease Activity (PGA)
Time Frame: Baseline to Week 24
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The physician assessed a participant's disease activity at the time of the visit using a Physician's Global Assessment of Disease visual analogue scale (VAS).
The range is 0 to 100 cm, with 0 representing no disease activity and 10 representing severe disease activity.
Negative values indicate improvement from baseline.
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Baseline to Week 24
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Change From Baseline in Morning Stiffness Severity
Time Frame: Baseline to Week 24
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Morning stiffness severity was assessed by a numeric rating-scale (NRS).
Participants rated the severity of morning stiffness during the past week from 0 to 10 with 0 representing "not severe" and 10 "very severe".
Negative values indicate improvement from baseline.
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Baseline to Week 24
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Percentage of Participants Achieving Low Disease Activity (LDA) Based on Clinical Disease Activity Index (CDAI) Criteria
Time Frame: Week 2 to Week 24
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The CDAI is a composite index for assessing disease activity based on the summation of the total tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), patient global assessment of disease activity measured on a VAS from 0 to 10 cm, and physician global assessment of disease activity measured on a VAS from 0 to 10 cm.
The total CDAI score ranges from 0 to 78 with higher scores indicating higher disease activity.
Low Disease Activity (LDA) based on CDAI is defined as achieving a total CDAI score of less than or equal to 10.
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Week 2 to Week 24
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Collaborators and Investigators
Investigators
- Principal Investigator: Zeng Xiaofeng Zeng, PhD, Peking Union Medical College
Study record dates
Study Major Dates
Study Start (Estimated)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- TLL-018-208
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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