A Study to Evaluate the Efficacy and Safety of HTMC0658 Tablets in the Treatment of Chronic Rhinosinusitis Without Nasal Polyps

A Phase IIa Clinical Study to Evaluate the Efficacy and Safety of HTMC0658 Tablets in the Treatment of Chronic Rhinosinusitis Without Nasal Polyps

The purpose of this clinical trial is to assess the efficacy and safety of HTMC0658 tablets in treating subjects with chronic rhinosinusitis without nasal polyps (CRSsNP).

Inclusion Criteria:

1. Subjects aged between 18 and 75 years, inclusive, of either sex.
2. Body Mass Index (BMI) calculated as weight in kilograms divided by the square of height in meters (kg/m²), with a BMI of at least 18.5.
3. Subjects must meet the diagnostic criteria for chronic rhinosinusitis as defined in the "Chinese Chronic Rhinosinusitis Diagnosis and Treatment Guidelines (2024)," with a disease duration exceeding 12 weeks.
4. During the screening period, nasal endoscopy must reveal bilateral pathological changes in the nasal mucosa, such as edema and purulent discharge, or a CT scan must show bilateral sinus involvement.
5. During the screening period, a CT scan must demonstrate bilateral sinus involvement, with at least one sinus on each side scoring ≥ 1 point on the Lund-MacKay (LMK) scale.
6. During the screening period, the Nasal Congestion Score (NCS) must be ≥ 2 points.
7. During the screening period, the Composite Symptom Score (CSS) for nasal congestion, rhinorrhea, and facial pain/pressure must be ≥ 5 points.
8. During the screening period, the Sino-Nasal Outcome Test-22 (SNOT-22) total score must be ≥ 20 points.
9. Subjects must have been on a stable daily dose of mometasone furoate nasal spray (MFNS) for at least 4 weeks prior to enrollment.
10. Subjects with asthma or chronic obstructive pulmonary disease (COPD) must have had stable conditions without exacerbations in the 3 months prior to screening (e.g., no emergency room visits, hospitalizations, or systemic corticosteroid use). The use of inhaled corticosteroids must have been at a stable dose, with continuous use for at least 3 months prior to screening, and planned continuation throughout the study period.
11. Subjects must fully understand the purpose, nature, methodology, and potential adverse events of the trial, voluntarily participate in the trial, and provide written informed consent, or have an authorized legal representative provide informed consent.

Exclusion Criteria:

1. Presence of nasal polyps confirmed by nasal endoscopy during the screening period, or a history of nasal polyps.
2. Requirement for systemic corticosteroids as maintenance therapy during the screening period.
3. Diagnosis of cystic fibrosis (CF) or primary ciliary dyskinesia.
4. Undergone nasal surgery within 4 weeks prior to screening, or scheduled for sinus surgery during the study period.
5. Presence of significant craniofacial structural abnormalities or severe nasal septal deviation.
6. Radiological suspicion or confirmed diagnosis of invasive fungal rhinosinusitis, odontogenic sinusitis, osteoma, or nasal tumor.
7. Presence of a disease or comorbidity that would interfere with the assessment of the primary efficacy endpoints (e.g., subjects with seasonal allergic rhinitis whose symptoms coincide with the study treatment period; subjects with moderate to severe atopic dermatitis requiring treatment with potent topical corticosteroids, topical calcineurin inhibitors, or biologics; subjects with acute upper respiratory tract infection that, in the investigator's judgment, would affect nasal symptom scoring).
8. Presence of an acute infection requiring antibiotic treatment within 4 weeks prior to screening.
9. Inflammatory or autoimmune diseases requiring systemic biologic therapy or immunosuppressive agents (including but not limited to immunodeficiency diseases).
10. Known allergy or intolerance to any component of the investigational medicinal product or background therapy.
11. Subjects with a past or current diagnosis of periodontitis or palmoplantar keratoderma due to functional deficiency of dipeptidyl peptidase 1 (DPP1), or the presence of the following at screening:a. Subjects with current signs of gingivitis/periodontitis.b. Subjects with a history of palmoplantar keratoderma or erythema.
12. Receipt of drugs that may cause skin hyperkeratosis (e.g., tumor necrosis factor-α antagonists) within 4 weeks prior to screening.
13. Patients who have used strong CYP3A4 or CYP2D6 inhibitors or inducers within 14 days prior to the first administration of the investigational medicinal product.
14. Subjects with elevated liver function test results during the screening period and currently requiring treatment for liver disease. Elevated liver function tests are defined as: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.0 × upper limit of normal (ULN), or total bilirubin (TBIL) > 1.5 × ULN.
15. Subjects with positive test results for hepatitis B surface antigen, hepatitis C virus antibody, human immunodeficiency virus antibody, and/or syphilis serology during the screening period.
16. Current smokers (defined as adults who have smoked at least 100 cigarettes in their lifetime and are currently smoking) or those who cannot abstain from smoking during the trial.
17. Subjects who have participated in other drug or medical device trials within 3 months prior to the start of this trial or are currently enrolled in another clinical trial.
18. Male subjects who plan to donate sperm or have a fathering plan from the start of dosing until 90 days after the last dose and are unwilling to use effective non-pharmacological contraceptive measures.
19. Female subjects who plan to donate oocytes or have a pregnancy plan from the start of dosing until 30 days after the last dose and are unwilling to use effective non-pharmacological contraceptive measures.
20. Pregnant or breastfeeding women.
21. Subjects whom the investigator deems unsuitable for participation in this study for any reason.