A Adaptive Design Clinical Trial to Evaluate the Efficacy and Safety of TDI01 Suspension in the Treatment of Idiopathic Pulmonary Fibrosis (IPF)

[Stage 1 study design] Stage 1 is divided into a screening period, a main study treatment period, an extension treatment period, and a safety visit period. Based on a previous Phase 2 study, it is planned to enrol 80 subjects.

All subjects who may participate in this study will enter the screening period (no more than 4 weeks) after voluntarily signing the informed consent form, and the investigator will assess the eligibility of the subjects according to the inclusion and exclusion criteria. All subjects will be re-assessed for eligibility before randomisation, and those who meet the criteria can enter the main study treatment period.

[Stage 2 study design] Stage 2 is divided into a screening period, a main study treatment period, an extension treatment period, and a safety visit period. It is initially planned to enrol 428 subjects, and the target population for both stages is the same.

The inclusion and exclusion criteria and randomisation procedure for the screening period of Stage 2 are the same as those for Stage 1. The main study treatment period is 52 weeks. The dosing regimen and dose adjustment plan for the investigational medicinal product in Stage 2 are the same as those in Stage 1. The proportion of subjects receiving IPF therapeutic drugs shall not be less than 40% of the total number of subjects.

Inclusion criteria

• Diagnosed with IPF

• Confirmed diagnosis before screening: Diagnosis was made according to the 2022 clinical practice guideline principles of the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Society (ALAT) (see Appendix 1), confirmed by the investigators based on chest high-resolution CT (HRCT) performed within 12 months before Visit 1, and surgical lung biopsy or transbronchial lung cryobiopsy (if available);
• Reconfirmation of IPF diagnosis at screening: And before Visit 2, the independent imaging review panel of experts reviewed and confirmed that the HRCT (HRCT within 3 months before randomisation in the same site was accepted) is consistent with a clinical diagnosis of usual interstitial pneumonia (UIP) or probable UIP for IPF. For subjects with an HRCT finding of "indeterminate for UIP", if a local (previous) surgical lung biopsy or transbronchial lung cryobiopsy has been performed, the pathological slides must be submitted for central review and assessment. If the histopathological features show "UIP" or "probable UIP", the clinical diagnosis of IPF can be confirmed;
• Voluntarily participates in this clinical study and signs the informed consent form before the start of the study;
• Age is 40-80 years (inclusive of 40 and 80 years) at the time of signing the informed consent form, regardless of sex;
• Female or male subjects of childbearing potential agree and commit to using highly effective contraceptive measures (see Appendix 8 in 19.8) from the time of signing the informed consent form until 90 days after the last dose of the investigational medicinal product;
• Stable disease for at least 8 weeks prior to Visit 1. Patients must meet one of the following two criteria:

• Did not receive treatment with nintedanib and/or pirfenidone for at least 8 weeks prior to Visit 1 (including patients not treated with nintedanib/pirfenidone and those who had failed treatment with nintedanib/pirfenidone);
• Or have been receiving a stable* regimen of nintedanib or pirfenidone for at least 12 weeks prior to Visit 1, and plan to continue receiving this background therapy stably after randomisation [*stable treatment is defined as the patient being able to generally tolerate continuous treatment with an unchanged dose of pirfenidone (400 mg TID and above) or nintedanib (100 mg BID and above)];
• At screening and baseline, forced expiratory volume in one second (FEV1)/FVC ratio ≥ 0.70;
• At screening and baseline, FVC% of predicted is greater than 50% (inclusive);
• DLco (Hb-corrected) percent of predicted normal value is greater than 30% (inclusive) at screening and at baseline;
• Active bacterial, viral, parasitic, or fungal infection requiring systemic treatment within 4 weeks prior to screening, but the infection is judged by the investigator to be cured during the screening period;
• In the investigator's assessment, the subject is willing and able to comply with protocol requirements and attend visits.

Exclusion criteria

Inclusion criteria

Subjects who meet each of the following criteria will be allowed to participate in this study:

• Diagnosed with IPF

• Confirmed diagnosis before screening: Diagnosis was made according to the 2022 clinical practice guideline principles of the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Society (ALAT) (see Appendix 1), confirmed by the investigators based on chest high-resolution CT (HRCT) performed within 12 months before Visit 1, and surgical lung biopsy or transbronchial lung cryobiopsy (if available);
• Reconfirmation of IPF diagnosis at screening: And before Visit 2, the independent imaging review panel of experts reviewed and confirmed that the HRCT (HRCT within 3 months before randomisation in the same site was accepted) is consistent with a clinical diagnosis of usual interstitial pneumonia (UIP) or probable UIP for IPF. For subjects with an HRCT finding of "indeterminate for UIP", if a local (previous) surgical lung biopsy or transbronchial lung cryobiopsy has been performed, the pathological slides must be submitted for central review and assessment. If the histopathological features show "UIP" or "probable UIP", the clinical diagnosis of IPF can be confirmed;
• Voluntarily participates in this clinical study and signs the informed consent form before the start of the study;
• Age is 40-80 years (inclusive of 40 and 80 years) at the time of signing the informed consent form, regardless of sex;
• Female or male subjects of childbearing potential agree and commit to using highly effective contraceptive measures (see Appendix 8 in 19.8) from the time of signing the informed consent form until 90 days after the last dose of the investigational medicinal product;
• Stable disease for at least 8 weeks prior to Visit 1. Patients must meet one of the following two criteria:

• Did not receive treatment with nintedanib and/or pirfenidone for at least 8 weeks prior to Visit 1 (including patients not treated with nintedanib/pirfenidone and those who had failed treatment with nintedanib/pirfenidone);
• Or have been receiving a stable* regimen of nintedanib or pirfenidone for at least 12 weeks prior to Visit 1, and plan to continue receiving this background therapy stably after randomisation [*stable treatment is defined as the patient being able to generally tolerate continuous treatment with an unchanged dose of pirfenidone (400 mg TID and above) or nintedanib (100 mg BID and above)];
• At screening and baseline, forced expiratory volume in one second (FEV1)/FVC ratio ≥ 0.70;
• At screening and baseline, FVC% of predicted is greater than 50% (inclusive);
• DLco (Hb-corrected) percent of predicted normal value is greater than 30% (inclusive) at screening and at baseline;
• Active bacterial, viral, parasitic, or fungal infection requiring systemic treatment within 4 weeks prior to screening, but the infection is judged by the investigator to be cured during the screening period;
• In the investigator's assessment, the subject is willing and able to comply with protocol requirements and attend visits.

Exclusion criteria

Subjects who meet any of the following criteria will not be allowed to participate in this study:

• Other known causes of interstitial lung disease, such as home or occupational environmental exposure, connective tissue disease, drugs, etc.;
• With other clinically significant lung diseases besides IPF (such as asthma, COPD or significant airways obstruction [FEV1/FVC ratio <0.7], hypersensitivity pneumonitis, eosinophilic pneumonia, etc.);
• Patients who are planning to undergo a lung transplant within 12 months after screening;
• Active infection tuberculosis within 12 months prior to screening, or any active bacterial, viral, parasitic, or fungal infection requiring systemic treatment during the screening period;
• Subjects whose IPF condition is assessed by the investigator as unstable at screening, or who have had an acute exacerbation of IPF within 8 weeks before screening and/or during the screening period;
• Use of any of the following treatments within 4 weeks prior to randomisation:

• IPF therapeutic drugs, unstable treatment with nintedanib or pirfenidone, > 15 mg/d prednisone or equivalent doses of other glucocorticoids, use of immunomodulatory drugs other than glucocorticoids for respiratory/pulmonary reasons; [Stable treatment is defined as the individual patient being able to generally tolerate continuous treatment with an unchanged dose of pirfenidone (400 mg TID and above) or nintedanib (100 mg BID and above) for at least 8 weeks];
• Strong CYP3A4 inhibitors (including but not limited to ritonavir, clarithromycin, idelalisib, etc., see Appendix 4 for details);
• Narrow therapeutic window substrates of CYP2C9 (such as warfarin, tolbutamide, and phenytoin) and sensitive substrates of P-gp (such as digoxin);
• ROCK2 inhibitor (belumosudil);
• History of malignant tumour within 5 years prior to screening (except for patients with appropriately treated skin basal cell carcinoma or squamous cell carcinoma of skin in situ or in situ cancer of cervix);
• Moderate to severe hepatic insufficiency (Child-Pugh Class B or C) before screening;
• Laboratory test results exceeding any of the following criteria at screening and at baseline: Bilirubin total >1.5×ULN or AST/ALT>2×ULN, serum CK>1.5×ULN;
• Uncontrolled hepatitis B virus infection (HBsAg positive and HBV-DNA ≥ 102 IU/mL) or hepatitis C virus infection (anti-HCV and HCV-RNA positive) at screening;
• With history of unstable or worsening cardiac disorder within 6 months prior to screening, including but not limited to the following:

• Unstable angina;
• Myocardial infarction;
• CCF requiring hospitalisation or NYHA Class III/IV;
• Uncontrolled severe arrhythmia.
• Family history of long QT syndrome or sudden death, or clinically significant abnormalities on ECG at screening and baseline, including but not limited to: QTcF interval > 470 ms (female) or >450 ms (male), fibrillation atrial or flutter atrial, second-degree or third-degree AV block, left bundle branch block;
• SBP >160 mmHg or DBP >100 mmHg at screening and baseline (to be measured after at least 5 minutes of rest, and confirmed by one re-check to still meet this standard);
• Cerebrovascular event leading to hospitalisation within 12 months prior to screening, including but not limited to hematencephalon, subarachnoid haemorrhage, stroke, etc.;
• Creatinine clearance (CLcr) <50 mL/min at screening and baseline, calculated using the Cockcroft-Gault formula: [140 - age (years)] [weight (kg)] × (0.85, if female) / [72 × blood creatinine (mg/dL)];
• Unable to complete the six minute walk distance (6MWD) or pulmonary function test (PFT);
• History of smoking within 3 months prior to screening or unwillingness to practice cessation of smoking during the study;
• Frequent alcohol use [more than 21 units of alcohol per week (1 unit = 360 mL beer or 45 mL of 40% alcohol or 150 mL wine)] within 6 months before screening, or unwillingness to reduce alcohol intake to within 21 units during the study;
• History of drug abuse within 6 months prior to screening;
• Pregnancy or lactation;
• Human immunodeficiency virus (HIV) antibody test result is non-negative at screening;
• Allergy to any component of TDI01 suspension;
• The last dose in other clinical studies was administered within 3 months or 5 half-lives prior to screening, whichever is longer;
• Major surgery (general anaesthesia surgery) within 3 months prior to screening, or planned surgery during the study period that is considered by the investigator to affect the judgment of study endpoints;
• The investigator assesses that the subject has an unstable state of other systemic or organ diseases, which may impair their safety or compliance, affect drug absorption, or lead to other conditions that prevent them from completing the study assessments.