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

Inclusion criteria

• Age ≥40 years, regardless of gender;
• Diagnosis of IPF confirmed prior to or during screening per the 2022 ATS/ERS/JRS/ALAT guidelines (Appendix 1);
• Patients must meet one of the following criteria:

• 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;
• 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];
• Percentage predicted forced vital capacity (FVCpp) ≥45% at screening;
• Percentage predicted diffusing capacity of the lungs for carbon monoxide (DLCOpp) ≥25% and <90% at screening [*hemoglobin (Hb)-adjusted];
• Willing to participate and voluntarily sign the informed consent form.

Exclusion criteria

• Clinically significant airway obstruction during screening [pre-bronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) <0.7];
• Other clinically significant pulmonary abnormalities per investigator judgment (exceptions: conditions requiring no treatment during the trial, e.g., asymptomatic pulmonary nodules, emphysema);
• Acute IPF exacerbation within 3 months before screening and/or during screening;
• Receiving immunomodulators (excluding oral corticosteroids) for respiratory conditions, or prednisone >15 mg/day (or equivalent);
• History of vasculitis;
• Any suicidal behavior within 2 years before screening (actual attempt, interrupted attempt, aborted attempt, or preparatory acts/behaviors);
• 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);
• Respiratory infection requiring antibiotics or other infections requiring treatment within 4 weeks before/during screening;
• Major surgery within 3 months before screening or planned during the study (investigator-assessed; lung transplant listing excluded);
• Malignancy within 5 years before screening (except treated basal cell carcinoma, squamous cell carcinoma in situ, or cervical carcinoma in situ);
• Blood pressure ≥160/100 mmHg at screening;
• Unstable/worsening cardiovascular/cerebrovascular disease within 6 months before screening (e.g., unstable angina, myocardial infarction, heart failure, thromboembolic events including stroke/TIA);
• Aspartate transaminase (AST) or alanine transaminase (ALT) >2.5×ULN or total bilirubin >1.5×ULN at screening;
• Estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m² at screening;
• Gastrointestinal surgery/disease affecting pharmacokinetics (PK) (except appendectomy/hernia repair);
• 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;
• Current treated liver disease with Child-Pugh A/B/C impairment at screening;
• 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;
• Tobacco/nicotine product use within 3 months before screening or unwillingness to abstain during the study;
• 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;
• Use of strong CYP3A4 inhibitors/inducers within 14 days or 5 half-lives (whichever longer) before first dose, or anticipated need during the study;
• History of severe drug allergy or hypersensitivity to investigational product/excipients;
• Participation in other clinical trials (receiving investigational drug/placebo) within 1 month before screening;
• Pregnancy/lactation; participants of childbearing potential unwilling to use contraception during and for 3 months post-study (including male participants);
• Any other investigator-determined factors making participation unsuitable.