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A1055 - Safety and Suitability of a Direct Thrombin Inhibitor, Dabigatran Etexilate, in Scleroderma-Associated Interstitial Lung Disease (SSc-ILD) Patients
Author Block: R. Silver1, I. Atanelishvili1, T. Akter1, K. Kajdasz1, D. Wilson2, P. Nietert3, J. T. Huggins4, K. B. Highland5, G. Bogatkevich1; 1Medicine/Rheumatology, Medical University of South Carolina, Charleston, SC, United States, 2Public Health Sciences, Medical University of South Carolina, Charleston, SC, United States, 3Public Health Sciences, Med Univ of South Carolina, Charleston, SC, United States, 4Medicine/Pulmonology, Med Univ of S Carolina, Charleston, SC, United States, 5Respiratory Institute/ Department of Pulmonary, Cleveland Clinic, Cleveland, OH, United States.
Background. Studies have shown thrombin to be implicated in the pathogenesis of ILD. Thrombin activity is elevated in SSc-ILD, and thrombin can transform normal lung fibroblasts to a myofibroblast phenotype. Strong preclinical in vitro and in vivo animal data demonstrate that a selective thrombin inhibitor, Dabigatran etexilate (Pradaxa®), can ameliorate lung fibrosis, which has led us to conduct a single-site, open-label study to establish the safety of Dabigatran etexilate in SSc-ILD patients.
Methods. Dabigatran etexilate (Pradaxa®), 75 mg bid for 6 months, is being administered to 15 patients with SSc-ILD (ClinicalTrials.gov Identifier NCT02426229). Safety and tolerability of Dabigatran etexilate therapy is the primary objective of this clinical trial. We are also conducting exploratory studies of potential effects on skin and lungs, including effects on the activity of thrombin in plasma and BALF, as well as the biologic behavior of skin and lung fibroblasts.
Results. 13 patients with SSc-ILD fulfilling the 2013 ACR/EULAR classification criteria have been enrolled thus far, with 11 having completed the 6-month treatment. Baseline characteristics are as follows: 11 females and 2 males; 6 African Americans and 7 Caucasians; 5 limited and 8 diffuse SSc; age 46.5 + 9.6 years (mean + SD); disease duration 4.25 + 3.47 years; skin score 15.9 + 11.0; Health Assessment Questionnaire 1.4 + 0.7; GI tract score 0.85 + 0.58; Baseline Dyspnea Index 7.8 + 3.4; FVC % predicted 70.8 + 6.2; DLCO % predicted 55.7 + 13.5. Overall, Dabigatran etexilate has been well tolerated with no serious adverse events. Mild adverse events include: headache (n=1), fatigue (n=1), epistaxis (n=2) and menorrhagia (n=1). Monthly laboratory monitoring has shown no clinically significant change in CBC, CMP, PT/INR or PTT. Exploratory analysis before and after Dabigatran etexilate treatment reveals that the most profound reduction in thrombin activity was observed in the patient having the highest concentration of active thrombin at baseline, and this patient also demonstrated the greatest reduction in collagen type I and α-smooth muscle actin in skin fibroblasts, as well as reduction of α-smooth muscle actin in lung fibroblasts.
Conclusions. Preliminary data suggest that Dabigatran etexilate is safe and well tolerated in patients with SSc-ILD. Exploratory analysis suggests that SSc-ILD patients with high thrombin activity may be the most likely to potentially benefit from treatment. A larger RCT is warranted to confirm safety and determine efficacy of Dabigatran in patients with SSc-ILD.