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Safety & Suitability of Dabigatran to Inhibit Thrombin in Scleroderma

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ClinicalTrials.gov Identifier: NCT02426229
Recruitment Status : Completed
First Posted : April 24, 2015
Last Update Posted : July 13, 2018
Sponsor:
Collaborator:
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Information provided by (Responsible Party):
Medical University of South Carolina

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Scleroderma Interstitial Lung Disease Drug: dabigatran etexilate Phase 1

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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety & Suitability of Dabigatran to Inhibit Thrombin in Scleroderma
Study Start Date : February 2016
Actual Primary Completion Date : June 2018
Actual Study Completion Date : June 21, 2018


Arm Intervention/treatment
Experimental: dabigatran 75mg
dabigatran etexilate 75mg orally twice daily for 6 months
Drug: dabigatran etexilate
dabigatran etexilate 75mg orally twice a day for 6 months
Other Names:
  • Dabigatran
  • Pradaxa




Primary Outcome Measures :
  1. Composite: Safety of dabigatran patients with scleroderma interstitial lung disease. (complete blood counts, comprehensive metabolic profile, and coagulation studies). [ Time Frame: Up to 6 months ]
    Subjects taking dabigatran will undergo monthly complete blood counts (white blood cell count, hemoglobin, hematocrit, platelet), comprehensive metabolic profile (sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, total bilirubin, AST, ALT, alkaline phosphatase, protein and albumin), and coagulation studies (prothrombin time, partial thromboplastin time and thrombin time). Women of child-bearing age will be required to have a urine pregnancy test monthly while receiving dabigatran.


Secondary Outcome Measures :
  1. Composite: Preliminary estimate of efficacy of dabigatran in scleroderma. (skin score and dermal fibroblast biology) [ Time Frame: Up to 6 months ]
    We will also include investigations of scleroderma skin (skin score and dermal fibroblast biology) together with studies of scleroderma lung fibroblasts, to obtain preliminary estimates of the effectiveness of dabigatran as a potential disease modifying drug for patients with SSc-ILD.



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02426229


Locations
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
Sponsors and Collaborators
Medical University of South Carolina
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Investigators
Principal Investigator: Richard M Silver, MD Medical University of South Carolina

Publications:
Responsible Party: Medical University of South Carolina
ClinicalTrials.gov Identifier: NCT02426229     History of Changes
Other Study ID Numbers: 1R21AR065089-01A1 ( U.S. NIH Grant/Contract )
1R21AR065089-01A1 ( U.S. NIH Grant/Contract )
First Posted: April 24, 2015    Key Record Dates
Last Update Posted: July 13, 2018
Last Verified: July 2018

Keywords provided by Medical University of South Carolina:
SSc
systemic sclerosis
cutaneous systemic sclerosis

Additional relevant MeSH terms:
Lung Diseases
Scleroderma, Systemic
Scleroderma, Diffuse
Scleroderma, Localized
Lung Diseases, Interstitial
Respiratory Tract Diseases
Connective Tissue Diseases
Skin Diseases
Dabigatran
Thrombin
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants
Hemostatics
Coagulants