HL-300 Ointment in Patients With Mild-to-Moderate Atopic Dermatitis

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase Ib/II Clinical Study to Evaluate the Safety and Efficacy of HL-300 Ointment in Patients With Mild-to-Moderate Atopic Dermatitis

This study is a randomized, double-blind, placebo-controlled, multicenter Phase Ib/II clinical study designed to evaluate the efficacy, safety, and PK characteristics of HL-300 ointment with different concentration regimens for mild-to-moderate AD.

In the study, it is planned to enroll approximately 148-156 trial participants, divided into two cohorts. Cohort 1: a randomized, double-blind, placebo-parallel controlled study design, planning to enroll 140 trial participants, randomized in a 1:1:1:1 ratio to the study group or placebo group, with baseline disease severity (mild [vIGA-AD = 2] and moderate [vIGA-AD = 3]) set as stratification factors to ensure balanced participant status across groups. Cohort 2: an open-label, intensive sampling design, planning to enroll 8 trial participants for each dosage strength, enrolled separately, with continuous dosing for 8 days.

The study includes a screening period, a treatment period, and a follow-up period. The quality management system for this trial aims to prospectively integrate quality by design into all aspects of the trial to ensure the rights and interests, safety, and well-being of trial participants, and to guarantee the reliability of the generated data and the scientific validity of the trial results. This system strictly adheres to the principles of ICH E6(R3) and ICH E8(R1), employing a risk-based and proportionate approach.

During the trial design phase, the investigators have systematically identified the critical to quality (CtQ) factors for ensuring the quality of this trial. Given the known safety profile of JAK inhibitors (e.g., infections, hematologic abnormalities, hepatic and renal function effects, thrombosis, etc.), the CtQ factors for this trial will specifically focus on:

• Trial participant safety: Identification, recording, assessment, and timely reporting of Adverse Events (AEs) and Serious Adverse Events (SAEs).
• Key efficacy data: Accuracy and integrity of data collection related to the primary and secondary endpoints of the trial (e.g., vIGA-AD, EASI, BSA, WI-NRS, DLQI, SCORAD, etc.).
• Critical processes: Strict adherence to inclusion/exclusion criteria during participant screening [e.g., exclusion of severe infections (including herpes zoster, tuberculosis, and other opportunistic infections) and active infections, hematologic toxicity (anemia, neutropenia), elevated transaminases, and high-risk thrombosis population], protocol-mandated laboratory tests (e.g., blood routine, blood biochemistry, urinalysis, coagulation function, etc.), completeness of randomization and blinding, concomitant medication management (e.g., contraindications for topical medications for AD or AD-related skin infections, systemic treatments for AD, systemic immunosuppressants or immunomodulators, other JAK inhibitors, etc.), rules for suspension/termination of dosing.

Inclusion Criteria:

1. Age ≥18 years and ≤75 years at the time of ICF signing, with no gender restriction

2. Meeting the Hanifin & Rajka diagnostic criteria for atopic dermatitis (AD) at screening, with a history of AD ≥ 6 months before screening, and the AD condition judged by the investigator to be stable within 4 weeks prior to ICF signing,.

3. vIGA-AD score of 2-3 at screening and baseline visits;

4. EASI score within the range of 5-21 at screening and baseline;

5. "Body Surface Area (BSA) affected by AD skin lesions meeting one of the following requirements at screening and baseline visits, with skin lesions suitable for topical treatment:

   • Cohort 1: BSA of 5% to 20%;
   • Cohort 2: BSA of 15% to 25%. "

6. Women of childbearing potential and men willing to use at least one highly effective method of contraception or practice abstinence from the time of informed consent signing until 3 months after the last dose of the investigational product

7. Those who voluntarily participate in the study and sign the informed consent form

Exclusion Criteria:

1. "Trial participants with any of the following medical histories or abnormal conditions at screening: (1) Skin lesions or abnormalities that may affect the assessment of the investigational product application site; (2) Clinically relevant skin diseases that are contraindicated for the study or affect the assessment of the application site, including but not limited to: psoriasis, acne, skin cancer; (3) Other autoimmune diseases besides AD, such as inflammatory bowel disease, rheumatoid arthritis, where the investigator believes the disease would unfavorably impact the assessment of this study; (4) Current or history of lymphoproliferative disorders, or signs or symptoms suggestive of possible lymphoproliferative disorders, including lymphadenopathy or splenomegaly; (5) Any malignancy, or any history of malignancy within 5 years prior to screening (except for completely resected cervical carcinoma in situ or non-metastatic cutaneous squamous cell carcinoma, basal cell carcinoma, or papillary thyroid carcinoma); (6) History of herpes virus infection within the past 6 months, or recurrent herpes zoster (≥2 episodes), disseminated herpes zoster, disseminated herpes simplex, or current inability to rule out herpes zoster or herpes simplex infection; (7) Systemic infection requiring hospitalization within 12 weeks prior to screening to baseline, or active bacterial, viral, fungal, parasitic, or other infections requiring anti-infective treatment within 4 weeks prior to screening to baseline; (8) Local active infection within 1 week prior to screening to baseline, such as active infected AD, or any superficial skin infection requiring oral or intravenous antibiotic, antifungal, or antiviral medication; (9) History of thrombotic events, including deep vein thrombosis and pulmonary embolism, or high-risk factors for thromboembolism (e.g., immobilization or prolonged bed rest), which is judged by the investigator's comprehensive clinical assessment to be unsuitable for participation in this study; (10) History of significant cardiovascular, neurological, respiratory, hematological, digestive, urinary, immune, or psychiatric diseases that the investigator believes may confound study results or affect drug absorption, distribution, metabolism, and excretion, or place the trial participant at undue risk; (11) History of drug abuse or substance abuse."
2. "Trial participants who have received any of the following treatments: (1) Use of topical skin products for AD or AD-related skin infections at the study application site within 2 weeks prior to baseline, including but not limited to: topical corticosteroids (TCS), topical calcineurin inhibitors (TCI), topical phosphodiesterase 4 (PDE-4) inhibitor ointments, topical antimicrobials, etc.; (2) Use of topical skin products containing chemically active ingredients (including but not limited to vitamin E cream, functional products containing niacinamide/urea/ceramide, excluding emollients without any chemically active ingredients) at the study application site within 1 week prior to baseline; (3) Use of systemic therapeutic drugs for AD within 4 weeks or 5 half-lives (whichever is longer) prior to baseline, including but not limited to systemic anti-infectives, PDE-4 inhibitors, and systemic traditional Chinese medicine or herbal medicines for AD; (4) Use of systemic or topical JAK inhibitors (such as ruxolitinib, tofacitinib, baricitinib, filgotinib, lestaurtinib, pacritinib, delgocitinib, upadacitinib, abrocitinib, etc.) within 12 weeks prior to baseline; (5) Use of sedating antihistamines within 2 weeks prior to baseline (Stable use of non-sedating antihistamines is permitted [dose stable for 2 weeks or 5 half-lives (whichever is longer) before the first study medication]); (6) Use of systemic immunosuppressants or immunomodulators (such as oral or injectable corticosteroids, methotrexate, cyclosporine, mycophenolate mofetil, and azathioprine) within 4 weeks or 5 half-lives (whichever is longer) prior to baseline; (7) Use of biologics (such as dupilumab) within 12 weeks or 5 half-lives (whichever is longer) prior to baseline; (8) Use of strong CYP450 inhibitors or inducers within 2 weeks prior to baseline, including but not limited to: nelfinavir, ritonavir, clarithromycin, itraconazole, nevirapine, and barbiturates; (9) Vaccination with live/attenuated live vaccines within 4 weeks prior to baseline, or planning to receive vaccination during the study period; (10) Sunbathing or phototherapy (including ultraviolet therapy, photochemotherapy, etc.) with AD therapeutic effects within 4 weeks prior to baseline;"
3. "Trial participants with any of the following laboratory and instrumental examination results:

(1) Any significant clinical and laboratory abnormalities that the investigator believes may affect trial participant safety, including but not limited to:

1. White blood cell count (WBC) < 3×109/L, absolute neutrophil count (ANC) < 1.5×109/L, absolute lymphocyte count (ALC) < 0.8×109/L, platelet count (PLT) < 100×109/L, hemoglobin (Hb) < 100 g/L;
2. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2× ULN, or total bilirubin (TBIL) ≥ 1.5× ULN;
3. Blood creatinine > 1.5× ULN; (2) Confirmed or suspected active tuberculosis, incompletely cured tuberculosis, or active Mycobacterium tuberculosis infection (except for trial participants with documented treatment proving adequate therapy, who may enter this study based on the medical judgment of the investigator and/or infectious disease specialist) judged by the investigator and/or infectious disease specialist (combining medical history, symptoms, signs, laboratory tests, tuberculosis screening tests, and imaging findings); (3) QT interval corrected by Fridericia formula (QTcF) ≥500 ms in 12-ECG results at screening; (4) Hepatitis B surface antigen (HBsAg) positive; HBsAg negative but hepatitis B core antibody (HBcAb) positive and HBV-DNA above detection limit, or human immunodeficiency virus antibody (HIV) positive, or anti-hepatitis C virus (HCV) antibody positive and HCV-RNA positive, or Treponema pallidum antibody positive (excluding trial participants with negative non-specific syphilis antibody results and judged by the investigator to have a past history of syphilis infection that has been cured);" 4.Known or suspected allergy to the investigational product or excipients in the investigational product; 5.Female trial participants who are suspected or known to be pregnant, breastfeeding, or planning pregnancy during the trial period; 6.History of major surgery within 4 weeks prior to baseline or planned surgery during the study; 7.Significant blood loss, received blood transfusion, or donated blood (≥400 mL) within 3 months prior to baseline; 8.Participation in other clinical trials within 3 months prior to baseline; 9.Weekly alcohol consumption greater than 14 units within 3 months prior to screening (1 unit of alcohol ≈ 360 mL beer or 45 mL spirits with 40% alcohol content or 150 mL wine); 10.Other conditions judged by the investigator to be unsuitable for participation in the study.