A Phase Ib/IIa Study Assessing the Rapid Onset Characteristics of TLL-018 for Moderate-to-Severe CSU With Inadequate Response to Second-Generation H1 Antihistamines

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase Ib/IIa Clinical Trial Assessing the Rapid Onset Characteristics of TLL-018 in Subjects With Moderate-to-Severe Chronic Spontaneous Urticaria Who Fail to Achieve Adequate Control With Second-Generation H1 Antihistamines

The goal of this clinical trial is to evaluate the rapid onset characteristics of TLL-018 in moderate-to-severe CSU with inadequate response to second-generation H1 antihistamines.

The main objectives are:

To evaluate the rapid onset characteristics of TLL-018 in participants with moderate-to-severe chronic spontaneous urticaria.

To evaluate the safety profile of TLL-018 in participants with moderate-to-severe chronic spontaneous urticaria.

To evaluate the pharmacokinetic (PK) profile of TLL-018 in participants with moderate-to-severe chronic spontaneous urticaria.

Participants will be randomly allocated at a 1:1:1 ratio to receive TLL-018 10 mg, TLL-018 20 mg, or placebo orally after meals.

Inclusion Criteria:

• Aged between 18 and 75.
• Diagnosis of CSU refractory to second-generation H1-AH.
• CSU diagnosis for ≥ 6 months.
• The presence of itch and hives despite current use of an approved dose of H1-AH for ≥ 6 weeks prior to screening visit.
• UAS7 score (range 0-42) ≥ 16 and itch component of UAS7 (ISS range 0-21) ≥ 8 during 7 days prior to randomization (Day 1), and ISS ≥2 on the day of randomization.
• Participants are required to take a stable standard dose of a second generation H1-AH concomitantly according to local guidelines.
• Willing and able to to comply with the study protocol and complete the participant diary throughout the study period. Participants shall have no more than one missing urticaria symptom score (morning or evening HSS score and ISS score) within 7 days prior to randomization, and no missing HSS score or ISS score on the day immediately before randomization..
• Women of Child Bearing Potential (WOCBP) should not be pregnant or breastfeeding and the pregnancy test should be negative before randomization.
• Participants (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.

Exclusion Criteria:

1. Participants who meet the diagnostic criteria for chronic spontaneous urticaria (CSU) shall be excluded if they present with any of the following conditions:

   • Progressive or uncontrolled symptoms of renal, hepatic, hematologic, gastrointestinal, endocrine, pulmonary, cardiovascular, neurological, psychiatric or cerebral disorders that, in the investigator's judgment, would expose the patient to unacceptable risk from study participation.
   • A well-defined underlying etiology of chronic urticaria other than CSU, such as inducible urticaria, including but not limited to dermatographism, cold contact urticaria, heat contact urticaria, delayed pressure urticaria, solar urticaria, vibratory angioedema, cholinergic urticaria, aquagenic urticaria, and contact urticaria.
   • Other diseases presenting with urticaria or angioedema symptoms, including but not limited to urticarial vasculitis, urticaria pigmentosa, erythema multiforme, mastocytosis, hereditary urticaria, drug-induced urticaria, and hereditary or acquired angioedema.
   • Other chronic pruritic diseases that may interfere with efficacy outcome assessment, such as psoriasis, atopic dermatitis, bullous pemphigoid, dermatitis herpetiformis, and senile pruritus.
   • History of any malignant neoplasm prior to screening, with the exception of non-melanoma skin cancer (NMSC) or basal cell carcinoma that has been adequately treated and deemed cured, cervical carcinoma in situ, or ductal carcinoma in situ of the breast.
   • History of lymphoproliferative disorders (including but not limited to Epstein-Barr virus-related lymphoproliferative disorders, lymphoma, leukemia, etc.); or signs or symptoms suggestive of active lymphoproliferative disorder.
   • History of cardiovascular or cerebrovascular events or related surgical procedures within 12 months prior to screening, including but not limited to myocardial infarction, unstable angina pectoris, acute coronary syndrome, cerebral hemorrhage, stroke, coronary artery stent implantation, percutaneous transluminal coronary angioplasty, and coronary artery bypass graft surgery.
   • History of thromboembolic events within 12 months prior to screening (e.g., pulmonary thromboembolism, deep vein thrombosis, mesenteric artery embolism); or current high-risk factors for thromboembolic diseases (e.g., immobilization within 12 weeks prior to screening, congenital or hereditary thrombophilia, antiphospholipid antibody syndrome, etc.).
   • History of gastrointestinal perforation, except for cases caused by appendicitis or trauma.
   • History of herpes zoster within 1 year prior to randomization; history of disseminated herpes zoster or recurrent herpes zoster at any time prior to randomization; history of disseminated herpes simplex at any time prior to randomization.
   • Positive HBsAg prior to randomization (or negative HBsAg with positive HBcAb and abnormal HBV-DNA test results), positive HCV antibody (with abnormal HCV-RNA test results), positive HIV antibody, or positive syphilis serological antibody; or known HIV infection or known immunodeficiency status.
   • Any severe or systemic infection (bacterial, fungal, viral, parasitic, etc.) requiring intravenous antimicrobial therapy or resulting in hospitalization within 4 weeks prior to randomization; or any other active or recent infection that, in the investigator's judgment, would expose the participating patient to unacceptable risk.
   • Tuberculosis-related exclusion: Medical history, symptoms and relevant test results (e.g., tuberculosis screening test, chest X-ray) at screening suggest active tuberculosis.
   • History of severe hematologic disorders (e.g., aplastic anemia, myelodysplastic syndrome) or any disease that may cause hemolysis or erythrocyte instability, such as malaria and hemolytic anemia.

2. Participants with any of the following prior therapies or concomitant medications cannot be enrolled:

   • Receipt of treatment with JAK inhibitors (e.g., tofacitinib, baricitinib, ruxolitinib, etc.) or BTK inhibitors (e.g., remibrutinib) within 4 weeks prior to randomization.
   • Receipt of any investigational medicinal product within 4 weeks or 5 elimination half-lives prior to randomization, whichever is longer.
   • Prior exposure to omalizumab or omalizumab biosimilars.
   • Use of biologic agents with potential therapeutic effect on chronic spontaneous urticaria (CSU) (e.g., dupilumab, GR1802, SYB507, etc.) within 3 months or 5 elimination half-lives prior to randomization, whichever is longer.
   • Receipt of immunosuppressive or immunomodulatory agents within 4 weeks prior to randomization, including but not limited to systemic corticosteroids, ciclosporin, Tripterygium wilfordii tablets, Tripterygium glycosides tablets, methotrexate, mycophenolate mofetil, azathioprine, tacrolimus, dapsone, sulfasalazine and hydroxychloroquine.
   • Receipt of Traditional Chinese Medicine (TCM) or Chinese patent medicine explicitly indicated for urticaria per the package insert, clinical practice guidelines or prescription, within 4 weeks prior to randomization.
   • Receipt of topical therapy or phototherapy for CSU within 2 weeks prior to randomization.
   • Underwent major surgery within 4 weeks prior to randomization, or is scheduled to undergo major surgery after study enrollment.
   • Received any live vaccine within 2 months prior to screening, or plans to receive any live vaccine during the study period.
   • Donated a total of ≥400 mL of blood, or received blood transfusion, within 3 months prior to randomization.
   • History of drug or alcohol abuse within 6 months prior to screening (defined as 14 units of alcohol per week; 1 unit = 17.7 mL of pure ethanol, equivalent to 357 mL of 5% ABV beer, 43 mL of 40% ABV liquor, or 147 mL of 12% ABV wine).

3. History of allergy to any component of the investigational medicinal product or H1-antihistamines, or history of anaphylactic shock.

4. Abnormal findings at screening that meet any of the following criteria:

   • Complete blood count (CBC): hemoglobin (Hb) < 90 g/L; or white blood cell (WBC) count < 2.5 × 10⁹/L; or absolute neutrophil count (ANC) < 1.5 × 10⁹/L; or absolute lymphocyte count (ALC) < 0.8 × 10⁹/L; or platelet (PLT) count < 100 × 10⁹/L.
   • Liver function: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 × upper limit of normal (ULN), or total bilirubin (TBIL) > 2 × ULN.
   • nSerum creatinine ≥ 1.2 × ULN.
   • Coagulation function: either prothrombin time (PT) or activated partial thromboplastin time (APTT) exceeds the ULN and is clinically significant.
   • Uncontrolled hypertension (systolic blood pressure [SBP] ≥ 160 mmHg and/or diastolic blood pressure [DBP] ≥ 100 mmHg). One repeat measurement shall be performed for confirmation: if the initial blood pressure reading exceeds the above threshold, a repeat test will be conducted after the participant has rested for at least 10 minutes; if the repeat result is below the threshold, the second measurement value shall be adopted.
   • Uncontrolled hyperlipidemia (fasting total cholesterol ≥ 7.2 mmol/L, or fasting low-density lipoprotein cholesterol [LDL-C] ≥ 4.9 mmol/L, or fasting triglycerides [TG] > 5.6 mmol/L).
   • Abnormal cardiac function, or clinically significant abnormal electrocardiogram (ECG) findings that are assessed by the investigator to pose unpredictable risks, such as severe arrhythmia.
   • Other abnormal examination findings that, in the investigator's judgment, may impair the participant's ability to complete the study or interfere with study outcomes.

5. Any other condition or circumstance that, in the investigator's judgment, renders the participant unsuitable for participation in this study.