A Trial to Compare Nintedanib With Placebo for Patients With Scleroderma Related Lung Fibrosis

Systemic Sclerosis (SSc) is a devastating disease of unknown etiology. Patients suffer from multiple organ fibrosis whereas lung fibrosis (interstitial lung disease, ILD) is one of the main driver for mortality. There is preclinical evidence for efficacy of nintedanib in SSc and associated ILD (SSc-ILD) and the anti-fibrotic efficacy of nintedanib was proven in idiopathic pulmonary fibrosis patients, who are presenting a similar pattern regarding lung fibrosis. Hence it is the purpose of the trial to confirm the efficacy and safety of nintedanib 150 mg bid in treating patients with SSc-ILD, compared with placebo. The trial will be conducted as a double blind, randomised, placebo-controlled trial with primary efficacy evaluation at week 52 and placebo-controlled treatment until last patient out (up to a maximum of 100 weeks). Respiratory function is globally accepted for assessment of treatment effects in patients with lung fibrosis. The chosen endpoint (Forced Vital Capacity (FVC) decline) is easy to obtain and is part of the usual examinations done in patients with SSc-ILD.


Eligibility Criteria:
Inclusion criteria:

* Age \>= 18 years
* 2013 American College of Rheumatology (ACR) / EULAR classification criteria for SSc fulfilled
* SSc disease onset (defined by first non-Raynaud symptom) within 7 years
* SSc related Interstitial Lung Disease confirmed by High Resolution Computer Tomography (HRCT); Extent of fibrotic disease in the lung \>= 10%
* FVC \>= 40% of predicted normal
* Carbon Monoxide Diffusion Capacity (DLCO) 30% to 89% of predicted normal

Exclusion criteria:

* Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) \>1.5 x ULN
* Bilirubin \>1.5 x ULN
* Creatinine clearance \<30 mL/min
* Airway obstruction (pre-bronchodilator Forced Expiratory Volume in 1 second (FEV1)/FVC \<0.7)
* Other clinically significant pulmonary abnormalities
* Significant Pulmonary Hypertension (PH)
* Cardiovascular diseases
* More than 3 digital fingertip ulcers or a history of severe digital necrosis requiring hospitalization or severe other ulcers
* Bleeding risk (such as predisposition to bleeding, fibrinolysis, full-dose anticoagulation, high dose antiplatelet therapy, history of hemorrhagic central nervous system (CNS) event within last year
* international normalised ratio (INR) \>2, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT) by \>1.5 x ULN)
* History of thrombotic event within last year
* Clinical signs of malabsorption or needing parenteral nutrition
* Previous treatment with nintedanib or pirfenidone
* Treatment with prednisone \>10 mg/day, azathioprine, hydroxychloroquine, colchicine, D-penicillamine, sulfasalazine, cyclophosphamide, rituximab, tocilizumab, abatacept, leflunomide, tacrolimus, newer anti-arthritic treatments like tofacitinib and cyclosporine A, potassium para-aminobenzoate
* Unstable background therapy with either mycophenolate mofetil or methotrexate
* Previous or planned hematopoietic stem cell transplantation
* Patients with underlying chronic liver disease (Child Pugh A, B, C hepatic impairment)