Safety and Efficacy of TollB-001 Tablets in Moderate to Severe Rheumatoid Arthritis

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase IIa Clinical Study to Evaluate the Efficacy and Safety of TollB-001 Tablets in Patients With Moderate to Severe Active Rheumatoid Arthritis

The goal of this study is to evaluate the safety, pharmacokinetic (PK) characteristics, and preliminary efficacy of a new oral chemical drug in : adults aged 18-70 years (male or female) with moderate to severe active rheumatoid arthritis (RA), who have had inadequate response to or intolerance of at least one conventional synthetic disease-modifying antirheumatic drug (csDMARDs) .

Participants will take the assigned study drug (either tollB-001 Tablets or placebo) once daily orally for 4 weeks, follow up for 1 week.

Inclusion Criteria:

1. Aged 18 to 70 years (inclusive) at the time of signing the informed consent form, regardless of gender.
2. Diagnosis of RA according to the 1987 American College of Rheumatology (ACR) criteria or the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria.
3. DAS28-CRP > 3.2 at screening (joints that have undergone major surgical treatment or intra-articular injection of glucocorticoids or hyaluronic acid within 6 weeks before randomization are not counted in the TJC and SJC counts).
4. C-reactive protein (CRP)/high-sensitivity C-reactive protein (hsCRP) ≥ upper limit of normal (ULN) at screening.
5. Prior to the first administration of the study drug, has received continuous treatment with at least one conventional synthetic disease-modifying antirheumatic drug (csDMARDs, including methotrexate, chloroquine, hydroxychloroquine, sulfasalazine, leflunomide, iguratimod) with inadequate response or intolerance, and agrees to discontinue use during the study.
6. Female and male subjects of childbearing potential must use effective contraceptive measures during the study and for 3 months after the last study drug administration. Male subjects whose spouses or partners are females of childbearing potential must also agree to use effective contraceptive measures during the study and for 3 months after the last administration, and shall not donate sperm during this period. Female subjects of childbearing potential must have a negative pregnancy test.
7. Must provide written informed consent and be willing and able to comply with the study protocol (e.g., understand and complete questionnaires, follow the visit schedule, take medications as prescribed).

Exclusion Criteria:

1. Hypersensitivity to the study drug or any of its components.

2. ACR functional class IV or being bedridden/wheelchair-bound for a long time.

3. Use of any of the following drugs or treatments:

   Prior use of Janus kinase (JAK) inhibitors (including but not limited to tofacitinib, baricitinib, upadacitinib), biologic disease-modifying antirheumatic drugs (bDMARDs), or participation in clinical trials of the aforementioned drugs.

   Use of csDMARDs within 28 days before randomization (leflunomide within 56 days before administration, or subjects who have received standard cholestyramine treatment or activated charcoal washout within 28 days are not eligible for enrollment).

   Use of other known drugs with strong immunosuppressive or immunomodulatory effects (such as puerarin, tripterygium wilfordii, mycophenolate mofetil, cyclosporine, tacrolimus, azathioprine, 6-mercaptopurine, etc.) other than the above within 4 weeks before randomization.

   Receipt of any parenteral (intramuscular or intravenous) or intra-articular glucocorticoids within 4 weeks before randomization.

   Receipt of interferon treatment within 4 weeks before randomization. Oral traditional Chinese medicine for the treatment of RA and other inflammatory diseases within 4 weeks before randomization.

   Use of opioid drugs within 1 week or 5 drug half-lives (whichever is longer) before the first administration of the study drug.

   Receipt of integrin αV antibodies or cell depletion therapy within 3 months or 5 half-lives (whichever is longer) before the screening visit.

4. History or evidence of any of the following diseases:

   Other systemic inflammatory diseases except RA (excluding secondary Sjögren's syndrome), including but not limited to juvenile chronic arthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, systemic lupus erythematosus, ankylosing spondylitis, reactive arthritis, systemic vasculitis, gout, or other joint diseases that may affect efficacy evaluation (e.g., osteoarthritis with significant joint pain).

   Felty's syndrome. Any active malignant tumor or history of malignant tumor. Chronic pain history that may affect study evaluation. Active tuberculosis, latent untreated tuberculosis, or incompletely cured tuberculosis as judged by the investigator and/or specialist.

   History of any persistent or chronic infection (e.g., chronic pyelonephritis, bronchiectasis, osteomyelitis) deemed inappropriate for study participation by the investigator, or oral anti-infective drugs (excluding onychomycosis) within 14 days before the first administration of the study drug; history of deep space/tissue infection (e.g., fasciitis, abscess, osteomyelitis) within 52 weeks before the screening visit.

   Poorly controlled severe diseases such as diabetes mellitus, hypertension, kidney disease, neurological disease, liver disease, severe heart disease (e.g., decompensated heart failure [New York Heart Association Class III or IV], unstable angina pectoris, myocardial infarction, etc.), respiratory disease, severe chronic gastrointestinal disease (e.g., active or recurrent peptic ulcer), or prior treatment that may affect drug absorption (e.g., gastrointestinal surgery) and deemed by the investigator to potentially hinder the subject's participation in the study.

   Major surgery within 8 weeks before randomization or expected to undergo major surgery after enrollment.

5. Any laboratory abnormalities meeting the following criteria at screening:

   Hemoglobin < 90.0 g/L. Total white blood cell count < 2.5 × 10⁹/L. Neutrophil count < 1.5 × 10⁹/L. Lymphopenia (lymphocyte count < 750 cells/μL). Platelet count < 100 × 10⁹/L.

6. Positive hepatitis B surface antigen (HBsAg); or positive hepatitis B core antibody (HBcAb) with HBV DNA above the lower limit of detection; positive hepatitis C virus (HCV) antibody with positive HCV-RNA; positive human immunodeficiency virus (HIV) antibody or positive syphilis antibody.

7. Drug or alcohol abuse or dependence at screening, or history of drug or alcohol abuse or dependence within 6 months before randomization.

8. Participation in any clinical trial of drugs or medical devices within 4 weeks or 5 half-lives (whichever is longer) before randomization.

9. Blood donation ≥ 400 mL or receipt of blood transfusion within 3 months before randomization.

10. Any other factors deemed by the investigator to potentially affect the conduct or result evaluation of the study.