A Phase 3 Study Comparing TLL-018 to Tofacitinib in RA Subjects With Inadequate Response or Intolerance to bDMARDs

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)

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.

Inclusion Criteria:

• Aged between 18 and 65;
• Meet the diagnostic criteria of rheumatoid arthritis of the American College of Rheumatology/European Alliance against Rheumatism (ACR/EULAR,2010) with duration of at least 3 months;
• Meet the criteria for active rheumatoid arthritis；
• Have received at least one kind of bDMARDs for three months or longer and show inadequate response or intolerance to at least one kind of bDMARDs；
• Meet the ACR (1991) grading criteria of grade I, II or III；
• Discontinuation of bDMARDs or JAK inhibitors for more than four weeks；
• To sustain a stable status, oral administration of stable doses of glucocorticoids (≤ prednisone 10 mg/day or equivalent corticosteroids) and stable doses of nonsteroidal anti-inflammatory drugs (NSAIDs) are allowed to use, provided that stable doses are maintained for at least one week prior to the study；
• BMI index is less than 35 kg/m2;
• Women of Child Bearing Potential (WOCBP) should not be pregnant or breastfeeding and the pregnancy test should be negative before randomization;
• Subjects (whether male or female) should have adequate barrier contraception during the whole treatment period and at least 90 days after treatment; subjects should avoid the sperm or ovum donation for at least six months after treatment；
• Subjects understand the informed consent form (ICF), volunteer for the study and sign the ICF;

Exclusion Criteria:

• With other rheumatic diseases;
• With other systemic inflammatory diseases;
• With progressive or uncontrolled symptoms of renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiovascular, neurologic, psychiatric, or cerebral disease;
• Previous history of severe hematologic diseases;
• Previous history of malignancy within five years, with exception of cured basal cell carcinoma or cutaneous squamous cell carcinoma or cervical carcinoma in situ.
• With active infection before randomization;
• Herpes zoster occurred within 1 year prior to randomization; disseminated or recurrent herpes zoster prior to randomization; disseminated herpes simplex before randomization;
• Previous history of active tuberculosis (TB) and no evidence of clinical cure or imaging evidence of active TB; or T-spot or PPD positive at screening but have received TB preventive therapy less than one month;
• HBsAg positive (or HBsAg negative but anti-HBc positive and HBV-DNA quantitative test positive), HCV antibody and HCV-RNA positive, or HIV antibody positive;
• Previous history of thrombocytopenia, coagulopathy, or platelet dysfunction;
• Previous history of cardiovascular and cerebrovascular accidents;
• Previous history of thromboembolism or risk factors;
• Previous history of gastrointestinal perforation;
• Temporary usage of NSAIDs within 48 hours prior to the baseline visit;
• Have received anti-rheumatic herb within 4 weeks before randomization;
• Have received interferon therapy within 4 weeks before randomization;
• Have donated blood more than 400 ml or received blood transfusion within 3 months prior to the study;
• Have received any live vaccine within 2 months before randomization or plan to receive a live vaccine during the study;
• Have experienced major surgery within 4 weeks before randomization, or expected to receive major surgical treatment after enrollment;
• Laboratory test results are abnormal and may interfere the study judged by investigators;
• Use of potent opioids within 4 weeks before the baseline visit;
• Allergy to ingredients or excipients of tofacitinib or TLL-018;
• Unable to accomplish evaluation in study;
• Receiving any study drug within 4 weeks or less than 5 elimination of half-life period) before randomization (whichever is longer);