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
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 90
- 试验地点
- 1
- 主要终点
- Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12
研究概览
简要总结
This is a randomized, double-blind, placebo-controlled parallel-group Phase II study. The study aims to evaluate the efficacy and safety of TLL-018 in adult patients with moderate to severe active rheumatoid arthritis who have inadequate response or intolerance to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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).
研究组 & 干预措施
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.
干预措施: Placebo (Drug)
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.
干预措施: TLL-018 (Drug)
结局指标
主要结局
Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 12
时间窗: Week 12
Participants who met all of the following 3 conditions for improvement from baseline were classified as achieving the ACR20 response criteria: 1. ≥ 20% improvement in tender joint count (68 joints); 2. ≥ 20% improvement in swollen joint count (66 joints); and 3. ≥ 20% improvement in at least 3 of the following 5 parameters: 1. Physician's Global Assessment of Disease Activity (PGA); 2. Patient's Global Assessment of Disease Activity (PtGA); 3. Patient self-assessed pain (VAS); 4. Health Assessment Questionnaire Disability Index (HAQ-DI); 5. High-sensitivity C-reactive protein (hsCRP); C-reactive protein (CRP) is also acceptable.
次要结局
- Percentage of Participants With an American College of Rheumatology 20/50/70% (ACR20/50/70) Response(Week 2 to Week 24 (ACR20, excluding Week 12))
- Change From Baseline in Disease Activity Score 28 (DAS28) (hsCRP)(Baseline to Week 24)
- Percentage of Participants Achieving Low Disease Activity (LDA) Based on DAS28(hsCRP)(Week 2 to Week 24)
- Percentage of Participants Achieving Clinical Remission Based on DAS28 (hsCRP)(Week 2 to Week 24)
- Change From Baseline in CDAI Scores(Baseline to Week 24)
- Change From Baseline in SDAI Scores(Baseline to Week 24)
- Change From Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI)(Baseline to Week 24)
- Change From Baseline in Duration of Morning Stiffness(Baseline to Week 24)
- Change From Baseline in Patient's Assessment of Pain(Baseline to Week 24)
- Change From Baseline in Patient's Global Assessment of Disease Activity (PtGA)(Baseline to Week 24)
- Change From Baseline in Physician's Global Assessment of Disease Activity (PGA)(Baseline to Week 24)
- Change From Baseline in Morning Stiffness Severity(Baseline to Week 24)
- Percentage of Participants Achieving Low Disease Activity (LDA) Based on Clinical Disease Activity Index (CDAI) Criteria(Week 2 to Week 24)