A Multicenter, Randomized, Blinded, Placebo- and Active-Controlled Phase II Study to Evaluate the Efficacy and Safety of SYH9061 in Adult Patients With Idiopathic Pulmonary Fibrosis

Inclusion Criteria:

1. Age ≥ 40 years, male or female;
2. According to the 2022 guidelines of the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association titled "Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults", the investigator confirms that the participant has a clinical diagnosis of IPF based on chest HRCT or surgical lung biopsy or transbronchial lung cryobiopsy (if available) during the screening period or within 1 year prior to screening;
3. Received a stable dose of a single anti-fibrotic therapy (pirfenidone or namilumab) for at least 8 weeks prior to screening and will continue after randomization, OR have not received stable anti-fibrotic therapy or have discontinued it for at least 8 weeks and do not plan to use anti-fibrotic therapy during the trial; for participants receiving background therapy, their compliance with background therapy within 8 weeks prior to screening must be ≥80% (i.e., the proportion of days the participant actually took the background medication to the days they should have taken it within 8 weeks prior to screening is not less than 80%);
4. Participants are able to correctly use a DPI for inhalation;
5. Able to perform acceptable and repeatable pulmonary function tests;
6. FVCpp ≥ 45% at screening;
7. Hemoglobin-corrected DLCOpp ≥ 25% and < 90% at screening;
8. Understand the purpose and risks of this study, understand and are willing to follow all study procedures, agree to participate in the study and sign written informed consent.

Exclusion Criteria:

1. Interstitial lung diseases other than IPF, including any other type of idiopathic interstitial pneumonia; interstitial lung disease associated with exposure to fibrogenic substances, other environmental toxins, or drugs; other types of occupational interstitial lung disease; granulomatous interstitial lung disease; pulmonary vascular disease; autoimmune-related interstitial lung disease, including vasculitis and connective tissue diseases, etc.;

2. Presence of airway obstruction (FEV₁/FVC < 0.7) at screening, or emphysema extent greater than pulmonary fibrosis extent on chest HRCT;

3. Known acute exacerbation of IPF or suspected acute exacerbation of IPF by the investigator within 3 months prior to screening (Definition of acute exacerbation of IPF: primarily assessed by the investigator, acute exacerbation is defined as an acute, clinically significant respiratory deterioration characterized by new widespread alveolar abnormality, accompanied by all of the following: acute worsening or development of dyspnea lasting within one month; new bilateral ground-glass opacities and/or consolidation on CT images consistent with IPF features; deterioration not fully attributable to heart failure or fluid overload);

4. The investigator judges, based on changes in FVC, DLCO, and/or chest HRCT results, that there has been continuous improvement in the severity of IPF during the 12 months prior to screening;

5. Presence of other clinically significant respiratory diseases at screening, including diseases of the airways, lung parenchyma, pleural cavity, mediastinum, diaphragm, or chest wall, which, in the investigator's judgment, may affect the study results;

6. Presence of any severe and/or uncontrolled disease that, in the investigator's judgment, affects drug evaluation, including but not limited to: severe neurological diseases (e.g., epilepsy, dementia, etc.), history of severe mental disorders, major cardiovascular diseases (including but not limited to: myocardial infarction within 6 months prior to screening, unstable angina within 1 month prior to screening), thrombotic events (including but not limited to stroke and transient ischemic attack within 6 months prior to screening), QTcF interval prolongation (males > 450 msec, females > 470 msec) or severe arrhythmias requiring pharmacological intervention, etc.;

7. Active peptic ulcer, active gastrointestinal bleeding, hemoptysis, or hematuria within 4 weeks prior to screening;

8. Received therapeutic doses of anticoagulation (including but not limited to vitamin K antagonists, therapeutic doses of oral anticoagulants, or therapeutic doses of low molecular weight heparin/unfractionated heparin) within 1 week prior to screening, excluding low-dose regimens for prophylactic anticoagulation or catheter locking; received high-dose platelet therapy within 2 weeks prior to screening; received fibrinolytic therapy within 4 weeks prior to screening; known genetic predisposition to bleeding based on the investigator's judgment;

9. Platelet count < 100×10^9/L, or those with known and potential bleeding risks;

10. Surgery requiring general anesthesia or hospitalization > 1 day within 8 weeks prior to screening or planned during the study period;

11. Severe pulmonary hypertension (concomitant use of epoprostenol/treprostinil parenteral therapy, or severe right heart failure);

12. History of malignancy: Patients with basal cell carcinoma, localized squamous cell carcinoma of the skin, or carcinoma in situ of the cervix can enter this study if at least 12 months have passed since completion of curative treatment prior to signing informed consent; patients with other malignancies can enter this study if at least 5 years have passed since completion of curative treatment prior to signing informed consent;

13. Clinically significant active bacterial, fungal, or viral infection (defined as requiring oral or intravenous antibacterial, antifungal, or antiviral treatment) from 2 weeks prior to the screening visit until randomization;

14. Any infectious disease screening indicator at screening meets the following criteria:

    1. HBsAg positive, and HBV DNA test result is above the lower limit of quantification or 1000 copies/mL (500 IU/mL), whichever is lower;
    2. If HBsAg is negative and HBcAb is positive, an additional HBV DNA test is required, and the result is above the lower limit of quantification or 1000 copies/mL (500 IU/mL), whichever is lower;
    3. If the HCV antibody test result is positive, an additional HCV RNA test is required, and the result is above the lower limit of quantification or 1000 copies/mL, whichever is lower;
    4. HIV antibody positive;
    5. Treponema pallidum antibody positive (if the treponemal serological test is positive, a further non-treponemal serological test should be performed; if the latter is negative and the investigator judges it as a past syphilis infection that has been cured, the participant meets the inclusion criteria);
    6. Active tuberculosis infection at screening (if it is old tuberculosis or the tuberculosis screening is positive at screening, but the investigator judges there is no evidence of active infection, this criterion is not applicable);

15. Use of P-gp inhibitors (e.g., ketoconazole, erythromycin, etc.) or inducers (e.g., rifampicin, carbamazepine, phenytoin, etc.) within 14 days or 5 half-lives (whichever is longer) before the first dose of the investigational drug, or unable to stop taking them during the study period;

16. Receiving immunomodulatory drugs (except oral corticosteroids) or prednisone > 15 mg/day or equivalent for respiratory or pulmonary reasons during the screening period;

17. Receiving biologics within 2 months or 5 half-lives (whichever is longer) prior to screening;

18. Receiving any form of stem cell therapy, immune cell therapy, or other cell therapy products within 6 months prior to screening;

19. Abnormal liver or kidney function at screening as follows: ALT, AST > 2×ULN, or TBIL > 1.5×ULN, or eGFR < 30 mL/min/1.73 m² (CKD-EPI equation);

20. Severe, drug-uncontrolled persistent elevation of blood pressure at screening (systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 100 mmHg);

21. History of smoking within 3 months prior to screening and unwilling to quit smoking during the study period (including e-cigarettes);

22. Allergy to SYH9061 or any of its excipients, allergy to nintedanib or nintedanib excipients, allergy to peanuts or soybeans, or a history of severe drug allergy;

23. Participated in any clinical study within 4 weeks prior to screening (except those who did not receive the investigational drug); or are still in the follow-up period of a clinical study or within 5 half-lives of the investigational drug (whichever is longer) prior to screening;

24. Use of drugs with the same target (nintedanib) within 8 weeks prior to screening;

25. Pregnant or lactating women, or women or men of childbearing potential who are unwilling to use strict contraception throughout the entire trial period and for 3 months after receiving the last dose of the investigational drug (including male participants);

26. Planning to donate sperm during the treatment period or within 3 months after the last dose of the investigational drug;

27. Other circumstances deemed unsuitable for participation in this clinical trial by the investigator.