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

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

This study was conducted in a randomized, double-blind, placebo-controlled design to evaluate the efficacy and safety of Genakumab injection in the treatment of CTD-ILD including Rheumatoid Arthritis associated Interstitial Lung Disease (RA-ILD) and Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD)

Inclusion Criteria:

1. Those who voluntarily sign informed consent and can complete the experiment according to the plan;
2. Age 18-75 years old (including upper and lower limits), both male and female;
3. 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;
4. Interstitial lung disease (ILD) was confirmed by HRCT within 12 months before screening.
5. FVC≥ 40% of the expected value during the screening period;
6. DLCO (using hemoglobin correction) ≥ 40% of the expected value during the screening period;
7. 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;
8. 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.

Exclusion Criteria:

1. Allergic to experimental drugs or biological agents; People who have previously known other severe allergic reactions;

2. Airway obstruction (FEV1/FVC<0.7 before bronchodilator use) or other lung abnormalities deemed clinically significant by the investigator or a history of asthma;

3. Those who have received any of the following drugs or treatments :

   1. Receiving prednisone >15mg/ day or equivalent dose of glucocorticoid within 2 weeks prior to randomization;
   2. Receive azathioprine, colchicine, D-penicillamine, sulfasalazine within 8 weeks before randomization;
   3. 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.

4. Combined with other rheumatic diseases, such as idiopathic inflammatory myopathy, systemic lupus erythematosus, Sjogren's syndrome, mixed connective tissue disease, systemic vasculitis;

5. Significant pulmonary hypertension, meeting one of the following conditions:

   1. Previous clinical or echocardiographic evidence of significant right heart failure;
   2. Right cardiac catheterization showed cardiac index ≤ 2 l/min/m2;
   3. Pulmonary hypertension requiring extraenteral treatment with eprostol/traprostacycline;

6. There are active bleeding diseases of internal organs, or have a serious bleeding tendency (such as hemophilia, etc.), or are undergoing anticoagulant treatment;

7. There are infections requiring systemic drug control within 7 days prior to screening; Diagnosed with active tuberculosis infection;

8. 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;

9. Previous stem cell therapy or any type of bone marrow transplant; Previous solid organ transplants; Long-term systemic use of glucocorticoids for other diseases;

10. There is a history of serious immunodeficiency, or other acquired or congenital immunodeficiency diseases;

11. History of malignant tumor within 5 years before screening;

12. Recipients of kidney dialysis;

13. Presence of the following clinically significant heart diseases:

    1. A history of chronic congestive heart failure, NYHA level IV; History of cardiac ejection fraction (EF) < 30% by echocardiography;
    2. Myocardial infarction, acute coronary syndrome, viral myocarditis, and pulmonary embolism occurred within 3 months; Coronary revascularization was performed within 6 months.
    3. 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;
    4. 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;

14. There are the following abnormalities in the laboratory test values during the screening period:

    1. White blood cell count <3×109/L, neutrophil count <1.5×109/L;
    2. PLT<75×109/L;
    3. Total bilirubin >1.5×ULN, alanine aminotransferase (ALT) >3×ULN, aspartate aminotransferase (AST) >3×ULN;
    4. Estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2;

15. History or current positive results of serum virology tests:

    1. hepatitis B surface antigen positive, or hepatitis B core antibody positive and HBV-DNA higher than the detection limit;
    2. Hepatitis C virus (HCV) antibody positive;
    3. Positive for human immunodeficiency virus (HIV) antibodies;
    4. Those who are positive for treponema pallidum antibodies and need treatment for syphilis infection.

16. Received treatment with any investigational drug or medical device in a clinical trial within 3 months prior to screening;

17. Pregnancy test positive during screening period; Lactating women;

18. The investigator assessed those who had other factors that made them unsuitable for participation in the trial