Study of the Efficacy of Nintedanib+Tocilizumab in Patients With Systemic Sclerosis and Interstitial Lung Disease

The study includes adult patients with systemic sclerosis (SSc) with interstitial lung disease (ILD) to evaluate the efficacy and safety of nintedanib plus tocilizumab combination therapy compared to standard therapy (methotrexate, mycophenolate mofetil) for 56 weeks.

Full title of the trial:

A multicentre clinical trial evaluating the safety and efficacy of the combination of nintedanib and tocilizumab compared to standard treatment in patients with systemic sclerosis and interstitial lung disease. Analysis with theranostic approach and assessment of cytokine activity, markers of inflammation and pulmonary fibrosis using computed tomography, positron emission tomography, and metabolome and transcriptome studies in selected patients. NINTOC-TU study.

Eligibility Criteria:
Inclusion Criteria:

1. Men or women aged 18-74 at the date of signing the informed consent.
2. Written informed consent in accordance with the International Harmonization Guidelines Harmonized Tripartite: Guidelines for Good Clinical Practice (ICH-GCP) and local regulations signed before any study procedure.
3. Documented diagnosis of systemic sclerosis according to the criteria of the American College of Rheumatology (ACR) and The European Alliance of Associations for Rheumatology (former name - European League Against Rheumatism) - EULAR, meeting the criteria of active disease \[patients with limited and diffused SSc)\] and with an overall disease duration of less than or equal to (≤ 72 months).
4. Patients with interstitial lung disease (ILD) confirmed by HRCT (min. 10% lung involvement).
5. Evaluation of skin induration with the modified Rodnan skin score (mRSS) from 10 to 45 units inclusive.
6. Patients treated with conventional drugs such as mycophenolate mofetil, methotrexate; should be on stable doses for ≥ 8 weeks before and including the screening visit (W0).
7. Patients may be treated with standard therapy, but no new therapy or withdrawal of therapy within 8 weeks before the first screening visit (W0).
8. Patients taking oral glucocorticosteroids (GCS) should be on a stable dose of ≤ 10 mg/day prednisone or equivalent for at least 8 weeks before the baseline visit.
9. Patients of childbearing potential should agree to abstain from sexual activity or use a highly effective method of contraception throughout the study and for at least 3 months after the last dose of medicinal products.

Exclusion Criteria:

1. Patients not fully capable of giving informed consent.
2. Pregnant or breastfeeding women.
3. Major surgery within 8 weeks before screening (W0A).
4. Rheumatic disease other than systemic sclerosis (systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease). Diagnosis of secondary Sjögren's syndrome is acceptable.
5. Active diverticulitis and severe enteritis.
6. Untreated lipid disorders (Initiation of treatment and modification of the lipid profile enable re-screening for examination after 8 weeks from the start of hypolipidemic treatment).
7. Immunization with a live or attenuated vaccine within 4 weeks before scheduled treatment.
8. Known hypersensitivity to human, humanized or murine monoclonal antibodies and hypersensitivity to peanut, soya.
9. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels greater than 1.5 times the upper limit of normal (ULN). If normalized, the patient may be considered for re-screening.
10. Bilirubin \>1.5 x ULN.
11. Creatinine clearance \<30 ml/min.
12. Significant pulmonary hypertension (PH).
13. Airway obstruction (forced expiratory volume before bronchodilation in 1 second (FEV1)/FVC \<0.7) and other clinically significant pulmonary abnormalities.
14. Cardiovascular diseases with heart failure NYHA III/IV.
15. More than 4 digital ulcers or a history of severe digital necrosis requiring hospitalization or severe other digital ulcers.
16. Bleeding risk (such as bleeding tendency, fibrinolysis, full dose of anticoagulants, high dose of antiplatelet therapy, history of central nervous system (CNS) bleeding events in the last year. (INR) \>2, prothrombin time (PT) and partial thromboplastin (PTT) \> 1.5 x ULN) and history of a thrombotic event within the last year, history of thrombosis still requiring full therapeutic anticoagulant therapy, fibrinolysis or high-dose antiplatelet therapy \> 150 mg ASA per day.
17. History of stroke, or myocardial infarction within 6 months before screening.
18. Prior treatment with pirfenidone or nintedanib if a minimum of 6 months had not been completed before enrolling the patient in the NINTOC-TU study.
19. Plasmapheresis and/or plasma exchange within the last 12 weeks before screening and use of immunoglobulins within the last 12 weeks and treatment with tocilizumab, treatments targeting B cell depletion, biologics (e.g. tumor necrosis factor antagonists), tyrosine kinase inhibitors, current treatment with alkylating agents (chlorambucil), autologous bone marrow transplantation, thalidomide, antithymocyte globulin, extracorporeal photopheresis.
20. Treatment with prednisone \>10 mg/day, azathioprine, hydroxychloroquine, colchicine, D-penicillamine, sulfasalazine if within 8 weeks before W0. Cyclophosphamide within \< 8 weeks of randomization visit (W 1). Rituximab within 6 months of visit (randomization W1).
21. Unstable (fluctuating) background therapy with mycophenolate mofetil or methotrexate in the last 8 weeks.
22. Patients with chronic liver disease (Child-Pugh A, B, C hepatic impairment).
23. Active or significant history of infection, including treatment with intravenous antibiotics within the last 4 weeks or oral antibiotics within 2 weeks before screening. Including active confirmed tuberculosis or latent tuberculosis without chemoprophylaxis following applicable local recommendations. Active infection with HBV, HCV, Herpes-Zoster virus in the last 12 months. Human Immunodeficiency Virus (HIV) infection.
24. A positive result of the SARS-CoV-2 PCR test during the "0" visit is an exclusion criterion, while a history of infection more than 4 weeks before the screening tests and confirmed by a negative SARS-CoV-2 PCR test is not an exclusion criterion.
25. Active or history of malignancy, except for excised/cured local basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ.
26. Active or past drug or alcohol abuse.
27. The inability to understand and comply with the requirements of the protocol (lack of compliance) excludes from participation in the study.