A Study to Evaluate the Efficacy, Safety, and Pharmacokinetic Profiles of TLL-018 in Patients With Moderate-to-Severe Atopic Dermatitis

A Phase II/III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Study to Evaluate the Efficacy, Safety, and Pharmacokinetic Profiles of TLL-018 in Patients With Moderate-to-Severe Atopic Dermatitis

This is an operationally seamless Phase II/III, multicenter, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe atopic dermatitis (AD). The Phase II stage aims to preliminarily evaluate the efficacy of TLL-018 and identify the dose and sample size for the subsequent Phase III stage, which is designed to confirm the efficacy of TLL-018.

The primary outcome measures are the proportion of participants achieving EASI-75 (≥75% improvement in Eczema Area and Severity Index from baseline) at week 16, and the proportion of participants achieving an Investigator's Global Assessment (IGA) score of 0 or 1 with a ≥2-point reduction from baseline at week 16.

Inclusion Criteria:

• The trial participant understands and voluntarily signs the informed consent form (ICF), and has the willingness and ability to complete the scheduled follow-up visits, treatment plans, laboratory tests, and other trial procedures required by the protocol.

• Male or female trial participants aged ≥18 and ≤75 years at the time of signing the ICF.

• Have a history of atopic dermatitis for at least 1 year at screening, and meet the Hanifin-Rajka diagnostic criteria.

• At screening and randomization, meet the criteria for moderate-to-severe atopic dermatitis as assessed by the investigator, with all of the following 4 conditions met simultaneously: Eczema Area and Severity Index (EASI) ≥16; Investigator's Global Assessment (IGA) ≥3; Body Surface Area (BSA) affected by atopic dermatitis ≥10%; Weekly average of Worst Itch Numeric Rating Scale (WI-NRS) ≥4.

  5. In the investigator's judgment, have received topical treatment for atopic dermatitis within 6 months prior to screening with inadequate clinical response or intolerance, or require systemic therapy to control the disease.

  6. The trial participant is able and willing to regularly use a mild emollient without active ingredients twice daily for at least 7 consecutive days prior to randomization, and to continue using it throughout the study.

  7. Female trial participants of childbearing potential must not be pregnant or lactating, and may enter the study only after pregnancy test results are confirmed negative.

  8. Female trial participants of childbearing potential, male trial participants, and their partners must use adequate and effective contraceptive measures from the screening period until 90 days after the last dose, and must have no plans to donate sperm (males) or ova (females) from the screening period until at least 6 months after the last dose.

Exclusion Criteria:

• Presence of any of the following diseases or medical histories:

  1. Inability to swallow investigational product, refractory nausea/vomiting, malabsorption, external biliary diversion; history of gastrointestinal perforation (excluding perforation secondary to appendicitis or mechanical trauma); gastrointestinal disorders impairing drug absorption or other malabsorption conditions.
  2. Concurrent active inflammatory skin diseases that may confound efficacy assessment.
  3. Current or prior lymphoproliferative disorders, or suggestive signs/symptoms including lymphadenopathy or splenomegaly.
  4. History of malignancy prior to screening, except for treated-and-cured non-melanoma skin cancer/basal-cell carcinoma, cervical carcinoma in-situ, or breast ductal carcinoma in-situ.
  5. Herpes zoster within 1 year before randomization; any prior disseminated or recurrent herpes zoster; any prior disseminated herpes simplex.
  6. Severe/systemic infections within 4 weeks pre-randomization requiring intravenous anti-infective therapy or resulting in infection-related hospitalization; or other active/recent infections judged by the investigator to confer unacceptable subject risk.
  7. Acquired or hereditary immunodeficiency disorders.
  8. Severe haematological diseases, or conditions predisposing to haemolysis or red-cell instability.
  9. Documented psychiatric disorders likely to impair trial compliance, or known poor adherence.
  10. Major surgery or severe trauma within 4 weeks pre-randomization, or planned major surgery during the trial.
  11. Prior or planned solid-organ transplantation (e.g., liver transplantation).
  12. History or evidence of high-risk cardiovascular/cerebrovascular disease.

• Any screening laboratory abnormality meeting the following thresholds:

  1. Complete blood count: haemoglobin < 90 g/L; white-blood-cell count < 2.5 × 10⁹/L; absolute-neutrophil count < 1.5 × 10⁹/L; lymphocyte count < 0.8 × 10⁹/L; platelet count < 100 × 10⁹/L.
  2. Liver function: AST or ALT > 2 × upper-limit-of-normal (ULN); total bilirubin > 2 × ULN.
  3. Serum creatinine ≥ 1.2 × ULN.
  4. Coagulation: PT or APTT > ULN with clinical significance.
  5. Uncontrolled hypertension: SBP ≥ 160 mmHg and/or DBP ≥ 100 mmHg. Confirmatory measurement: if initial reading exceeds threshold, rest ≥ 5 minutes then re-measure once; use repeat value if below threshold.
  6. Uncontrolled dyslipidaemia: fasting total cholesterol ≥ 7.2 mmol/L, or fasting LDL-C ≥ 4.9 mmol/L, or fasting triglycerides > 5.6 mmol/L.

• Tuberculosis-related exclusion criteria:

  1. History of active TB without documented clinical cure.
  2. Screening imaging (e.g., chest-CT) demonstrating active TB.
  3. Suspicious TB-related symptoms that cannot be ruled out by investigator (low-grade fever, cough, night-sweats, weight loss etc.).
  4. Latent tuberculosis infection (LTBI): positive TB assay (T-SPOT-TB, QuantiFERON-TB-Gold etc.) without active-TB signs/symptoms.

• Progressive/uncontrolled renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, cardiovascular, neurological, psychiatric or cerebral disease; investigator judges participation poses unacceptable risk.

• Known or suspected hypersensitivity to TLL-018 active substance, excipients, or agents of the same drug class.