A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and Safety of HSK44459 Tablets in Patients With Idiopathic Pulmonary Fibrosis

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Evaluate the Efficacy and Safety of HSK44459 Tablets in Patients With Idiopathic Pulmonary Fibrosis

This study aims to evaluate the efficacy and safety of HSK44459 tablets in patients with idiopathic pulmonary fibrosis (IPF).

Inclusion Criteria:

1. Age ≥40 years, regardless of gender;

2. Diagnosis of IPF confirmed prior to or during screening per the 2022 ATS/ERS/JRS/ALAT guidelines (Appendix 1);

3. Patients must meet one of the following criteria:

   1. No treatment with nintedanib or pirfenidone for at least 8 weeks prior to screening (e.g., treatment-naïve or discontinued therapy), with no plans to initiate or resume antifibrotic treatment;
   2. On a stable regimen of nintedanib or pirfenidone for at least 12 weeks prior to screening, without combination therapy with both drugs. [Stable therapy is defined as maintaining a constant dosage with tolerable drug-specific adverse events];

4. Percentage predicted forced vital capacity (FVCpp) ≥45% at screening;

5. Percentage predicted diffusing capacity of the lungs for carbon monoxide (DLCOpp) ≥25% and <90% at screening [*hemoglobin (Hb)-adjusted];

6. Willing to participate and voluntarily sign the informed consent form.

Exclusion Criteria:

1. Clinically significant airway obstruction during screening [pre-bronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) <0.7];
2. Other clinically significant pulmonary abnormalities per investigator judgment (exceptions: conditions requiring no treatment during the trial, e.g., asymptomatic pulmonary nodules, emphysema);
3. Acute IPF exacerbation within 3 months before screening and/or during screening;
4. Receiving immunomodulators (excluding oral corticosteroids) for respiratory conditions, or prednisone >15 mg/day (or equivalent);
5. History of vasculitis;
6. Any suicidal behavior within 2 years before screening (actual attempt, interrupted attempt, aborted attempt, or preparatory acts/behaviors);
7. Type 4 or 5 suicidal ideation per Columbia-Suicide Severity Rating Scale (C-SSRS) within 3 months before/during screening (active suicidal thoughts with method/intent but no plan, or with method/intent/plan);
8. Respiratory infection requiring antibiotics or other infections requiring treatment within 4 weeks before/during screening;
9. Major surgery within 3 months before screening or planned during the study (investigator-assessed; lung transplant listing excluded);
10. Malignancy within 5 years before screening (except treated basal cell carcinoma, squamous cell carcinoma in situ, or cervical carcinoma in situ);
11. Blood pressure ≥160/100 mmHg at screening;
12. Unstable/worsening cardiovascular/cerebrovascular disease within 6 months before screening (e.g., unstable angina, myocardial infarction, heart failure, thromboembolic events including stroke/TIA);
13. Aspartate transaminase (AST) or alanine transaminase (ALT) >2.5×ULN or total bilirubin >1.5×ULN at screening;
14. Estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m² at screening;
15. Gastrointestinal surgery/disease affecting pharmacokinetics (PK) (except appendectomy/hernia repair);
16. Active hepatitis B [HBsAg-positive with HBV-DNA above ULN], hepatitis C antibody-positive, syphilis (anti-TP-positive with TRUST above ULN), or HIV infection (anti-HIV-positive) at screening;
17. Current treated liver disease with Child-Pugh A/B/C impairment at screening;
18. Substance abuse, drug use, or excessive alcohol intake (>2 units/day; 1 unit=360 mL beer [5%], 45 mL spirits [40%], or 150 mL wine) within 3 months before screening;
19. Tobacco/nicotine product use within 3 months before screening or unwillingness to abstain during the study;
20. Previous HSK44459 use or PDE1/3/4/10/non-selective PDE inhibitor treatment (excluding HSK44459, e.g., apremilast, roflumilast, ibudilast) within 8 weeks before screening;
21. Use of strong CYP3A4 inhibitors/inducers within 14 days or 5 half-lives (whichever longer) before first dose, or anticipated need during the study;
22. History of severe drug allergy or hypersensitivity to investigational product/excipients;
23. Participation in other clinical trials (receiving investigational drug/placebo) within 1 month before screening;
24. Pregnancy/lactation; participants of childbearing potential unwilling to use contraception during and for 3 months post-study (including male participants);
25. Any other investigator-determined factors making participation unsuitable.