A Phase Ⅱa Study of ND-003 Tablets in Patients With Idiopathic Pulmonary Fibrosis

• Aged ≥40 years (inclusive, based on the date of signing the informed consent form), with no restriction on sex.

• Confirmed diagnosis of idiopathic pulmonary fibrosis (IPF) based on multidisciplinary discussion (MDD), with all of the following criteria met:

  1. Based on a comprehensive assessment of detailed medical history, physical examination, and relevant laboratory tests, the investigator must exclude interstitial lung diseases (ILDs) caused by other known factors, such as occupational or environmental exposures, genetic or familial factors, drug-induced lung injury, and connective tissue disease-associated ILD.
  2. High-resolution computed tomography (HRCT) must demonstrate a typical usual interstitial pneumonia (UIP) pattern, characterized by subpleural and basal-predominant honeycombing, with or without traction bronchiectasis or bronchiolectasis.

For participants with a typical UIP pattern on HRCT, a diagnosis of IPF can be established without lung biopsy. For participants with a probable UIP pattern on HRCT and corresponding clinical features (e.g., age 60 years, male sex, and a history of smoking), the diagnosis of IPF may be established following MDD evaluation. For participants with a probable UIP pattern on HRCT but without corresponding clinical features, an indeterminate UIP pattern, or findings suggestive of an alternative diagnosis, further examinations, such as bronchoalveolar lavage (BAL), transbronchial lung biopsy (TBLB), or surgical lung biopsy (SLB), may be considered. The final diagnosis should be determined through a comprehensive MDD assessment.[Reference: 2022 American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) Clinical Practice Guideline for the Diagnosis of Idiopathic Pulmonary Fibrosis.

• Participants must meet either of the following conditions:

  1. Have not received treatment with nintedanib, pirfenidone, or nerandomilast for at least 8 weeks prior to screening and throughout the screening period, and do not plan to initiate or reinitiate antifibrotic therapy; or
  2. Have received a single stable treatment regimen of nintedanib, pirfenidone, or nerandomilast for at least 8 weeks prior to screening and throughout the screening period. Stable treatment is defined as the participant being able to generally tolerate pirfenidone ≥400 mg TID, nintedanib ≥100 mg BID, or nerandomilast 18 mg BID, or the prescribed dose, with no dose changes for at least 8 consecutive weeks.
• Percent predicted forced vital capacity (FVCpp) ≥45% during the screening period.
• Hemoglobin-corrected percent predicted diffusing capacity of the lungs for carbon monoxide (DLCOpp) ≥25% during the screening period.
• Female participants of childbearing potential (excluding women who have undergone surgical sterilization and women who have been postmenopausal for at least 1 year) must have a negative serum pregnancy test within 72 hours prior to the first administration of the investigational product. Female participants of childbearing potential must agree to remain abstinent or use a highly effective method of contraception from the time of signing the informed consent form until 6 months after the last administration of the investigational product.
• Male participants of reproductive potential must agree to use effective contraception from the time of signing the informed consent form until at least 6 months after the last administration of the investigational product and must not donate sperm during this period.
• Participants must fully understand the study prior to participation and voluntarily sign a written informed consent form.

Exclusion Criteria:

• Known hypersensitivity to any component of ND-003 tablets.
• Acute exacerbation of pulmonary fibrosis within 3 months prior to screening.
• Presence during the screening period of any clinically significant major pulmonary disease or condition other than IPF, including but not limited to: active lung cancer; uncontrolled persistent asthma; acute exacerbation of chronic obstructive pulmonary disease; severe pneumonia requiring hospitalization or intravenous anti-infective therapy within 4 weeks prior to screening; or any other major pulmonary disease that, in the investigator's judgment, may significantly interfere with assessment of study endpoints, increase the risk to the participant, or affect pulmonary function or imaging assessments, such as active pulmonary tuberculosis, diffuse alveolar hemorrhage, pulmonary vasculitis, clinically significant pulmonary hypertension, or other respiratory failure requiring long-term oxygen therapy or mechanical ventilation.
• Major surgery within 4 weeks prior to the first dose, or planned surgery during the study period.
• Planned lung transplantation within 12 months after the first dose.
• Active pulmonary tuberculosis within 12 months prior to screening, or any active bacterial, viral, parasitic, or fungal infection requiring systemic treatment during the screening period.
• Receipt of a live vaccine within 4 weeks prior to the first dose, or planned receipt of a live vaccine during the study period. Live vaccines include, but are not limited to, vaccines against measles, mumps, rubella, varicella, yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid.
• Use of systemic glucocorticoids, either orally or by injection, for any reason within 4 weeks prior to the first dose at a dose exceeding prednisone 15 mg/day or an equivalent dose, for more than 7 consecutive days. Dose equivalence shall be calculated with oral prednisone as the reference, where intravenous methylprednisolone 4 mg is equivalent to oral prednisone 5 mg, and dexamethasone 0.75 mg is equivalent to oral prednisone 5 mg. The following is excluded from this criterion: routine use of inhaled glucocorticoids in participants with stable disease where, in the investigator's judgment, such treatment does not affect participant safety or study assessments, such as maintenance treatment for concomitant chronic obstructive pulmonary disease or asthma.
• Use, for respiratory or pulmonary indications, of immunomodulatory agents other than glucocorticoids within 4 weeks or 5 half-lives prior to the first dose, whichever is longer, including but not limited to cyclophosphamide, mycophenolate mofetil, azathioprine, cyclosporine, tacrolimus, rituximab, and JAK inhibitors, regardless of dose or treatment duration.
• Use within 7 days prior to the first dose of concomitant medications known to prolong the QT interval and/or strong inhibitors and/or inducers of CYP2C8 or CYP3A, or anticipated need for continued use of any of the above medications during the study.
• History of malignancy within the past 5 years, except for malignancies considered to be at very low risk after curative treatment, such as cervical carcinoma in situ, non-melanoma skin cancer, localized prostate cancer, and ductal carcinoma in situ.

• Laboratory test results at screening or baseline exceeding any of the following thresholds:

  1. Liver function: total bilirubin >1.5 × ULN, or AST or ALT >2 × ULN, or serum CK >1.5 × ULN;
  2. Hematology: hemoglobin \<9 g/dL, platelet count \<90 × 10\^9/L, or white blood cell count \<4.0 × 10\^9/L;
  3. Renal function: eGFR \<60 mL/min/1.73 m², calculated using the CKD-EPI equation.

• History of unstable or worsening cardiac disease within 6 months prior to screening, including but not limited to any of the following:

  1. Unstable angina;
  2. Myocardial infarction;
  3. Congestive heart failure requiring hospitalization or New York Heart Association (NYHA) Class III or IV heart failure;
  4. Uncontrolled severe arrhythmia, such as symptomatic ventricular tachycardia or atrial fibrillation that cannot be adequately controlled with medication.
• History of pancreatitis associated with prior use of tyrosine kinase inhibitors, or current evidence of mild to moderate pancreatitis.
• Family history of long QT syndrome or sudden death, or clinically significant electrocardiographic abnormalities at screening or baseline, including but not limited to: QTcF interval >470 ms in females or >450 ms in males, atrial fibrillation or atrial flutter, second- or third-degree atrioventricular block, or left bundle branch block.
• Echocardiographic evidence of a left ventricular ejection fraction (LVEF) \<50% or below the lower limit of normal, whichever threshold is higher.
• Systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at screening or baseline, measured after at least 5 minutes of rest and confirmed by one repeat measurement.
• Inability to swallow oral medication; presence of clinically significant gastrointestinal abnormalities, such as status post gastrointestinal resection, status post gastrointestinal anastomosis, chronic diarrhea, or intestinal obstruction; or any condition that, in the investigator's judgment, may severely impair gastrointestinal absorption.
• History of smoking within 3 months prior to screening, or unwillingness to abstain from smoking during the study.
• Known alcohol or drug dependence.
• Positive human immunodeficiency virus (HIV) antibody test; active syphilis; positive hepatitis C virus antibody with a positive hepatitis C virus (HCV) RNA result; or active hepatitis B, defined as positive hepatitis B surface antigen (HBsAg) with HBV DNA ≥ the upper limit of normal.
• Female participants who are pregnant or breastfeeding, or who plan to become pregnant during the study.
• Participation in any clinical study within 4 weeks prior to the first dose.
• Any other condition that, in the investigator's judgment, may affect participant compliance or render the participant unsuitable for participation in this study.