Safety & Suitability of Dabigatran to Inhibit Thrombin in Scleroderma

Condition(s) targeted: Scleroderma; Interstitial Lung Disease

Intervention: dabigatran etexilate (Drug)

Phase: Phase 1

Status: Not yet recruiting

Sponsored by: Medical University of South Carolina

Official(s) and/or principal investigator(s):
Richard M Silver, MD, Principal Investigator, Affiliation: MUSC

Overall contact:
Kelley Gibson, Phone: 843-792-5290, Email: gibsonke@musc.edu

This study evaluates if dabigatran etexilate is safe for use in patients with Scleroderma and Interstitial Lung Disease. All patients will receive 75mg of dabigatran etexilate twice a day for 6 months.

Official title: Safety & Suitability of Dabigatran to Inhibit Thrombin in Scleroderma

Study design: Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Primary outcome: Composite: Safety of dabigatran patients with scleroderma interstitial lung disease. (complete blood counts, comprehensive metabolic profile, and coagulation studies).

Secondary outcome: Composite: Preliminary estimate of efficacy of dabigatran in scleroderma. (skin score and dermal fibroblast biology)

Detailed description: 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.

Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

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

Kelley Gibson, Phone: 843-792-5290, Email: gibsonke@musc.edu

Related publications:

Bogatkevich GS, Ludwicka-Bradley A, Silver RM. Dabigatran, a direct thrombin inhibitor, demonstrates antifibrotic effects on lung fibroblasts. Arthritis Rheum. 2009 Nov;60(11):3455-64. doi: 10.1002/art.24935.

Starting date: June 2015
Last updated: April 23, 2015