Anlotinib Capsules in the Treatment for IPF/PF-ILDs

A Multicenter, Randomized, Double-blind, Placebo-controlled Clinical Trial of Anlotinib Capsules for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)/Progressive Fibrosis-interstitial Lung Disease (PF-ILDs)

This is an exploratory Phase 2 study evaluating the use of Anlotinib hydrochloride capsules for the treatment of IPF/PF-ILDs, with forced vital capacity (FVC) as the primary efficacy endpoint.

Drug: Anlotinib The dose of anlotinib hydrochloride is 8 mg per dose, taken orally once daily before breakfast. The treatment schedule is 2 consecutive weeks of dosing followed by a 1-week break.

The primary endpoint of this study is the change from baseline in forced vital capacity (FVC) at Week 24. Blinded treatment continues through Week 52 to evaluate longer-term efficacy and safety of anlotinib in the treatment of IPF/PF-ILDs, including the change from baseline in FVC at Week 52 as a secondary/supportive endpoint. After Week 52, all subjects may enter an extension period if they wish. If a dose is missed and the next scheduled dose is due within 12 hours, the missed dose should not be taken.

Drug: Placebo Placebo is taken orally once daily before breakfast, following the same schedule: 2 consecutive weeks of dosing followed by a 1-week break.

Consistent with the study design, the primary endpoint is the change from baseline in FVC at Week 24. Blinded placebo administration continues through Week 52 to support the evaluation of longer-term efficacy and safety, with the change from baseline in FVC at Week 52 as a secondary/supportive endpoint. After Week 52, all subjects may enter an extension period if they wish. If a dose is missed and the next scheduled dose is due within 12 hours, the missed dose should not be taken.

FVC stands for forced vital capacity, which is the maximum amount of air that can be forcefully exhaled after a deep inspiration, performed as quickly and completely as possible. This measure assesses lung function and is the core endpoint for evaluating treatment effects in this study.

Inclusion Criteria:

1. The participants voluntarily joined the study and signed an informed consent form. They showed good compliance throughout the study.

2. The study includes individuals aged 40-85 years old, of any gender, with an expected lifespan of over 1 year.

3. Subjects who meet either of the following two criteria: a. HRCT results confirming IPF diagnosis within the past 5 years and HRCT results within the past 12 months showing a range of parenchymal fibrotic changes between ≥10% and <50%, with less than 25% honeycombing change in the lung, and no other facilitating factors (e.g. asbestos exposure, allergic pneumonia, systemic sclerosis, rheumatoid arthritis) as detailed in Annex 1A. b. PF-ILDs: Patients with characteristics of fibrotic lung disease (see Annex 1B), and at least one of the following diagnostic criteria is met: i. Relative decline in FVC% predicted by ≥10% within 6 months; ii. Relative decline in FVC% predicted by ≥5-10% with worsening respiratory symptoms, or an increase in the degree of fibrosis on chest HRCT; ii. Worsening respiratory symptoms combined with an increase in the degree of fibrosis on chest HRCT;

4. Carbon monoxide diffusion capacity (DLco) (corrected for hemoglobin) between 30% and 80% of predicted value;

5. Forced vital capacity (FVC) ≥ 45% predicted;

6. The 6MWT distance is ≥ 150 meters

7. Arterial partial pressure of oxygen (PaO2) ≥ 60 mmHg (measured at sea level atmospheric pressure, at rest, and breathing room air)

8. "Major organ functions are good, and meet the following criteria: a. Standard blood routine examination (not corrected by blood transfusion or hematopoietic growth factor drugs in the past 7 days): hemoglobin (HGB) ≥ 90 g/L; absolute neutrophil count (NEUT) ≥ 1.5 × 10^9/L; platelet count (PLT) ≥ 90 × 10^9/L; b. Biochemical examination should meet the following criteria: total bilirubin (TBL) ≤ 1.5 times the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance rate (Ccr) ≥ 60 ml/min; c. Coagulation function or thyroid function examination should meet the following criteria: prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5 × ULN (not receiving anticoagulation therapy) or stable use of anticoagulants in the 2 weeks before enrollment; d. Thyroid-stimulating hormone (TSH) ≤ ULN after standard treatment; if abnormal, T3 and T4 levels should be investigated and can be enrolled if T3 and T4 levels are normal.

   e. Echocardiography evaluation: Left ventricular ejection fraction (LVEF) ≥50%

9. Female participants of childbearing potential must agree to use contraception (such as intrauterine device, contraceptive pill, or condom) during the study and for 6 months after the end of the study; must have a negative serum pregnancy test within 7 days before study entry and must not be lactating. Male participants must agree to use contraception during the study and for 6 months after the end of the study.

Exclusion Criteria:

1. Patients with acute exacerbation of IPF/PF-ILDs.;

2. Multiple factors that affect oral medication (such as dysphagia, chronic diarrhea, and intestinal obstruction)

3. Received major surgical treatment, incisional biopsy, or significant traumatic injury within 28 days prior to the start of the study treatment.

4. Long-standing non-healing wound or fracture.

5. Patients who have experienced thrombotic events, such as cerebrovascular accidents (including transient ischemic attacks, cerebral hemorrhage, and cerebral infarction), deep vein thrombosis, and pulmonary embolism, within the past 6 months, or those with other bleeding tendencies.

6. Subjects with any severe or uncontrolled comorbidities or undergoing immunotherapy, such as:

   1. Blood pressure remains uncontrolled even after antihypertensive therapy (systolic blood pressure ≥150mmHg or diastolic blood pressure ≥100mmHg); 2nd-degree myocardial ischemia or myocardial infarction, arrhythmia (including QTc ≥450ms (men), QTc ≥470ms (women)) or 2nd-degree congestive heart failure (New York Heart Association (NYHA) classification); pulmonary or systemic infections within 4 weeks before enrollment;
   2. Severe pulmonary arterial hypertension (systolic pulmonary artery pressure (SPAP) ≥70mmHg);
   3. Renal failure requiring hemodialysis or peritoneal dialysis;
   4. History of immune deficiency diseases, including HIV-positive or other acquired or congenital immune deficiency diseases, or history of organ transplantation;
   5. Known clinically significant liver disease history, including viral hepatitis, known carriers of hepatitis B virus (HBV) must exclude active HBV infection, i.e., HBV DNA positive (>2500 copies/mL or >500IU/mL, and greater than the upper limit of normal); known hepatitis C virus (HCV) infection and positive HCV RNA (>1×103 copies/mL), or other decompensated liver diseases;
   6. Fasting blood glucose (FBG) >10mmol/L after administration of hypoglycemic drugs (poor blood glucose control patients);
   7. Urine routine test indicates urine protein ≥+, and 24-hour urine protein quantitation is confirmed to be >1.0g.

7. Received high-dose steroids (e.g. prednisone >15mg/kg) within 1 month prior to randomization；

8. Use of immunosuppressants within 1 month prior to randomization after enrollment;

9. Long-term use (>1 week) of drugs such as amiodarone that may cause pulmonary fibrosis prior to enrollment;

10. Received interferon, N-acetylcysteine (>1800mg), or other anti-fibrotic drugs within 1 month prior to randomization

11. Prior treatment with nintedanib or pirfenidone is allowed only if discontinued at least 28 days before randomization; patients with a washout period of less than 28 days are excluded.

12. Participation in other drug trials within 3 months prior to randomization

13. The researcher considers any ineligible candidates.