Safety & Suitability of Dabigatran to Inhibit Thrombin in Scleroderma

Skin and pulmonary fibrosis result in substantial morbidity in scleroderma (SSc).
Furthermore, interstitial lung disease (ILD) culminating in pulmonary fibrosis is a major
cause of death among scleroderma patients. Studies implicate the coagulation system, most
notably the serine protease thrombin, in the pathogenesis of SSc-ILD. Thrombin can transform
normal lung fibroblasts to a scleroderma fibroblast phenotype. Dabigatran etexilate is a
selective thrombin inhibitor which is FDA-approved for the prevention of thromboembolic
complications in patients with atrial fibrillation. Dabigatran etexilate needs to be studied
as a potential anti-fibrotic agent for the treatment of SSc-ILD. This study is designed to
see if dabigatran etexilate is safe for use in patients with scleroderma. If so, the long
term goal of this study is to determine whether or not the fundamental results will translate
to a potential clinical intervention for SSc-ILD which can be tested in a future randomized
control trial.

Inclusion Criteria:

- Age ≥ 18 and ≤ 70 years

- All patients must fulfill the ACR/EULAR criteria for SSc. Patients may have limited
(cutaneous thickening distal, but not proximal to elbows and knees, with or without
facial involvement) or diffuse (cutaneous thickening proximal to elbows and knees,
often involving the chest or abdomen) cutaneous SSc, or systemic sclerosis sine
scleroderma

- SSc for less than 7 years, with onset defined as the date of the first non-Raynaud
phenomenon manifestation.

- All patients must have interstitial lung disease defined by any ground glass on HRCT
and >20% involvement of HRCT by pulmonary fibrosis and/or FVC <70% predicted

Exclusion Criteria:

- Inability to sign consent

- Currently enrolled in another clinical trial

- FVC < 40% predicted and/or DLCO (corrected for hemoglobin) < 30% of predicted
(suggesting severe probably irreparable disease)

- Other serious concomitant medical illnesses (e.g., cancer) limiting life expectancy to
<1 year at time of enrollment

- FEV1/FVC ratio < 65% (suggesting obstructive disease)

- Clinically significant pulmonary hypertension requiring treatment, based on the
clinician's judgment.

- Smoking of cigars, pipes or cigarettes within 3 months prior to and during enrollment

- Clinically significant abnormalities on chest x-ray other than interstitial lung
disease (e.g., lung mass, evidence of active pulmonary infection, emphysema)

- Use of prednisone (or equivalent) in doses > 10 mg daily within 3 months prior to and
during enrollment

- Use of colchicine, D-penicillamine, cyclophosphamide, mycophenolate mofetil,
azathioprine, endothelin receptor antagonists, phosphodiesterase type-5 inhibitors,
prostanoids, tyrosine kinase inhibitors, sirolimus, rituximab, perfinidone or other
"disease modifying medications" within 3 months prior to and during enrollment

- Pregnancy or lack of use of birth control method in women of childbearing age or
lactating

- Liver disease or increased baseline liver enzyme levels (ALT >3 x upper limit of
normal)

- Use of CYP450 inhibitors/inducers

- Hemoglobin < 10g/L

- If of child bearing potential, unwillingness to employ a reliable means of
contraception (condom, abstinence, IUD, tubal ligation, vasectomy)

- Active infection

- Creatinine clearance <30 ml/min

- Post transplantation

- Active medical and psychiatric conditions which the investigator may consider would
interfere with the subject's treatment, assessment, or compliance with the protocol

- Anticoagulation-related exclusions include:

1. Current anticoagulation therapy with warfarin

2. Increased risk of bleeding (e.g., uncorrectable inherited or acquired bleeding
disorder)

3. Platelet count <100,000/cmm or hematocrit <30% or > 55%

4. History of severe gastrointestinal bleeding within 6 months of screening

5. Known gastric antral vascular ectasia (GAVE) or gastric/intestinal
arterial-venous malformations (AVMs)

6. History of CVA within 6 months of screening

7. History of risks of falls as judged by the PI

8. Surgery or major trauma within the past 30 days

9. Any condition that, in the determination of the PI, is likely to require
anticoagulation therapy during the study

10. Clopidogrel, prasugrel or other anti-platelet therapy within 6 months of
screening

11. Aspirin therapy >325 mg daily

12. Therapy with other thrombin inhibitors