A Randomized, Double-blind, Placebo-controlled Phase II Clinical Study to Evaluate the Safety, Tolerability, Efficacy, and Pharmacokinetic Profile of Genakumab Injection in Patients With Connective Tissue Disease-associated Interstitial Lung Disease

Prior treatment

• Allergic to experimental drugs or biological agents; People who have previously known other severe allergic reactions;
• Significant pulmonary hypertension, meeting one of the following conditions:
  • Previous clinical or echocardiographic evidence of significant right heart failure;
  • Right cardiac catheterization showed cardiac index ≤ 2 l/min/m2;
  • Pulmonary hypertension requiring extraenteral treatment with eprostol/traprostacycline;
• There are infections requiring systemic drug control within 7 days prior to screening; Diagnosed with active tuberculosis infection;
• Have received live or attenuated vaccine within 3 months prior to screening, or plan to receive live or attenuated vaccine during the study period; Vaccination against COVID-19 within 2 weeks prior to screening;
• Previous stem cell therapy or any type of bone marrow transplant; Previous solid organ transplants; Long-term systemic use of glucocorticoids for other diseases;
• Received treatment with any investigational drug or medical device in a clinical trial within 3 months prior to screening;

Other illness

• Airway obstruction (FEV1/FVC\<0.7 before bronchodilator use) or other lung abnormalities deemed clinically significant by the investigator or a history of asthma;
• Combined with other rheumatic diseases, such as idiopathic inflammatory myopathy, systemic lupus erythematosus, Sjogren's syndrome, mixed connective tissue disease, systemic vasculitis;
• There are active bleeding diseases of internal organs, or have a serious bleeding tendency (such as hemophilia, etc.), or are undergoing anticoagulant treatment;
• There is a history of serious immunodeficiency, or other acquired or congenital immunodeficiency diseases;
• History of malignant tumor within 5 years before screening;

Lab values

• Those who have received any of the following drugs or treatments :
  • Receiving prednisone \>15mg/ day or equivalent dose of glucocorticoid within 2 weeks prior to randomization;
  • Receive azathioprine, colchicine, D-penicillamine, sulfasalazine within 8 weeks before randomization;
  • received rituximab, tolizumab, nidanib, pirfenidone and other treatments within 6 months before randomization; Abacil, TNF inhibitors and other biologic agents were received within 3 months before randomization; Tofaciib, tacrolimus, cyclosporin A, and potassium para-aminobenzoate were used 30 days or 5 half-lives prior to screening, whichever was older.
• Presence of the following clinically significant heart diseases:
  • A history of chronic congestive heart failure, NYHA level IV; History of cardiac ejection fraction (EF) \< 30% by echocardiography;
  • Myocardial infarction, acute coronary syndrome, viral myocarditis, and pulmonary embolism occurred within 3 months; Coronary revascularization was performed within 6 months.
  • There are severe arrhythmias that require Class Ia or III antiarrhythmic drugs; Arrhythmias with diseased sinus syndrome, grade II type II or grade III atrioventricular block, and no pacemaker implanted;
  • During the screening period, electrocardiogram indicated QTcF interval ≥ 480 ms (according to Fridericia correction formula, where QTcF=QT/RR\^0.33), or a history of prolonged QTc interval;
• There are the following abnormalities in the laboratory test values during the screening period:
  • White blood cell count \<3×109/L, neutrophil count \<1.5×109/L;
  • PLT\<75×109/L;
  • Total bilirubin \>1.5×ULN, alanine aminotransferase (ALT) \>3×ULN, aspartate aminotransferase (AST) \>3×ULN;
  • Estimated glomerular filtration rate (eGFR) \< 60 ml/min/1.73m2;
• History or current positive results of serum virology tests:
  • hepatitis B surface antigen positive, or hepatitis B core antibody positive and HBV-DNA higher than the detection limit;
  • Hepatitis C virus (HCV) antibody positive;
  • Positive for human immunodeficiency virus (HIV) antibodies;
  • Those who are positive for treponema pallidum antibodies and need treatment for syphilis infection.

Other

• Recipients of kidney dialysis;
• Pregnancy test positive during screening period; Lactating women;
• The investigator assessed those who had other factors that made them unsuitable for participation in the trial

• Those who voluntarily sign informed consent and can complete the experiment according to the plan;
• Age 18-75 years old (including upper and lower limits), both male and female;
• Rheumatoid arthritis (RA) diagnosed according to the 2010 American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) classification, or Systemic sclerosis (SSc) according to the 2013 ACR/EULAR classification;
• Interstitial lung disease (ILD) was confirmed by HRCT within 12 months before screening.
• FVC≥ 40% of the expected value during the screening period;
• DLCO (using hemoglobin correction) ≥ 40% of the expected value during the screening period;
• Patients may receive 1 immunosuppressant and must maintain a stable dose for 3 months prior to the first dose and agree to maintain a stable dose for at least 6 months after the first dose;
• Subjects of childbearing age who do not plan to become pregnant or donate sperm/eggs and agree to use reliable contraception during the period of participation in this trial and within 6 months after the last dosing.