clinical trial evaluating the efficacy of nintedanib with tocilizumab compared to standard treatment in patients with systemic sclerosis and interstitial lung disease

Prior treatment

• History of stroke, myocardial infarction within 6 months prior to screening.
• Prior treatment with pirfenidone and nintedanib if a minimum of 6 months had not been completed prior to enrolling the patient in the NINTOC-TU study.
• Plasmapheresis and/or plasma exchange within the last 12 weeks prior to 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.
• Treatment with prednisone >10 mg/day, azathioprine, hydroxychloroquine, colchicine, D-penicillamine, sulfasalazine if within 8 weeks prior to W0. Cyclophosphamide within < 8 weeks of randomization visit (W 1). Rituximab within 6 months of visit (randomization W1).
• Unstable (fluctuating) background therapy with mycophenolate mofetil or methotrexate in the last 8 weeks.
• Active or significant history of infection, including treatment with intravenous antibiotics within the last 4 weeks or oral antibiotics within 2 weeks prior to screening. Including active confirmed tuberculosis or latent tuberculosis without chemoprophylaxis in accordance with applicable local recommendations. Active infection with HBV, HCV, Herpes-Zoster virus in the last 12 months. Human Immunodeficiency Virus (HIV) infection.
• 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.
• Active or past drug or alcohol abuse.
• Major surgery within 8 weeks prior to screening (W0A).
• Immunization with a live or attenuated vaccine within 4 weeks prior to scheduled treatment.

Other illness

• Significant pulmonary hypertension (PH).
• Cardiovascular diseases with heart failure NYHA III/IV.
• More than 4 digital ulcers or a history of severe digital necrosis requiring hospitalization or severe other digital ulcers.
• Patients with chronic liver disease (Child Pugh A, B, C hepatic impairment).
• Active or history of malignancy, except for excised/cured local basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ.
• Rheumatic disease other than systemic sclerosis (systemic lupus erythematosus, rheumatoid arthritis, mixed connective tissue disease), diagnosis of secondary Sjögren's syndrome is acceptable.
• Untreated lipid disorders (initiation of treatment and modification of the lipid profile enables re-screening for examination, rescreaning, after 8 weeks from the start of hypolipidemic treatment).
• Known hypersensitivity to human, humanized or murine monoclonal antibodies and hypersensitivity to peanut, soya.

Lab values

• Bilirubin >1.5 x ULN.
• Creatinine clearance <30 ml/min.
• 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.
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) >1.5 x ULN, if normalized, patient may be considered for re-screening.

Other

• Patients not fully capable of giving informed consent.
• Airway obstruction (forced expiratory volume before bronchodilation in 1 second (FEV1)/FVC <0.7) and other clinically significant pulmonary abnormalities.
• Pregnant or breastfeeding women.
• The inability to understand and comply with the requirements of the protocol (lack of compliance) excludes from participation in the study.
• Active diverticulitis and severe enteritis.

• Men or women aged 18-74 at the date of signing the informed consent.
• Written informed consent in accordance with the International Harmonization Guidelines Harmonized Tripartite Guidelines for Good Clinical Practice (ICH-GCP) and local regulations signed prior to any study procedure.
• 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 an active disease [patients with limited and generalized TUu)] and with an overall disease duration of less than or equal to (≤ 72 months)..
• Patients with interstitial lung disease (ILD) confirmed by HRCT (min. 10% lung involvement).
• Evaluation of skin induration with the modified Rodnan scale (mRSS) from 10 to 45 units inclusive.
• Patients treated with conventional drugs such as mycophenolate mofetil, methotrexate; should be on stable doses for ≥ 8 weeks prior to and including the baseline visit (W0).
• Patients may be treated with standard therapy, but no new therapy or withdrawal of therapy within 8 weeks prior to the first screening visit (W0).
• Patients taking oral corticosteroids (GCS) should be on a stable dose of ≤ 10 mg/day prednisone or equivalent for at least 8 weeks prior to the baseline visit.
• 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.