Nilotinib in the Treatment of Systemic Sclerosis

Study Overview
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Brief Summary
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A phase IIa open-label single center pilot study to assess the safety and efficacy of Nilotinib in patients with Scleroderma.

Detailed Description
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The purpose of this study is to learn how safe and tolerable a medication called Nilotinib (Tasigna) will be for patients diagnosed with Systemic Sclerosis. Systemic Sclerosis (scleroderma) is an autoimmune disease that can involve the skin, the blood vessels, the muscles and other connective tissues, and major organs including the lungs, kidneys, gastrointestinal tract, and heart. The exact cause of this disorder is not known at this time and no drug has been proven to cure scleroderma. Experiments done in animal models and test-tube models of fibrosis suggest that Nilotinib may be a useful therapy for scleroderma. Nilotinib is a medication on the market which has been FDA approved for the treatment of a type of leukemia called chronic myelogenous leukemia (CML). It is an oral medication, taken two times a day. This is a 32 week, open-label, Phase IIa, single center clinical trial. The primary goal of the study is to assess the safety and tolerability of Nilotinib in patients with scleroderma. The secondary goal is to assess how effective Nilotinib is in treating patients with scleroderma. The clinical tests performed such as the Modified Rodnan Skin Score, Pulmonary Function Tests, Echocardiograms, Electrocardiograms, and the blood and skin collected in this study will help determine whether this therapy is safe and effective, and also improve our understanding of scleroderma.

Official Title
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Phase IIA Study of the Safety and Tolerability of the Use of Nilotinib in the Treatment of Systemic Sclerosis

Conditions
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Systemic Sclerosis

Intervention / Treatment
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* Drug: Nilotinib (Tasigna)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than or equal to eighteen years. Clinical diagnosis of diffuse systemic sclerosis by ACR criteria, with a stable modified Rodnan skin score in the one month preceding introduction of oral nilotinib therapy. The modified Rodnan skin score must be greater than or equal to sixteen at screening and initiation of therapy. Disease duration of less than or equal to 3 years as defined by the date of onset of the first non-Raynaud's symptom. Estimated ejection fraction of greater than 50% by echocardiography Exclusion Criteria: Inability to render informed consent in accordance with institutional guidelines. Disease duration of greater than 3 years. Patients with mixed connective tissue disease or overlap (i.e. those who satisfy more than one set of ACR criteria for a rheumatic disease.) Limited scleroderma. Systemic sclerosis-like illness associated with environmental or ingested agents such as toxic rapeseed oil, vinyl chloride, or bleomycin. Ongoing treatment with immunosuppressive therapies including cyclophosphamide, azathioprine, mycophenolic acid, methotrexate, or cyclosporine, or use of those medications within 1 month of trial entry. The use of other anti-fibrotic agents including colchicine, D-penicillamine, minocycline, or Type 1 oral Collagen in the month prior to enrollment. Use in the prior month of corticosteroids at doses exceeding the equivalent of prednisone 10 mg daily. Use of corticosteroid at < 10 mg of prednisone can continue during the course of the study. Concurrent serious medical condition which in the opinion of the investigator makes the patient inappropriate for this study such as uncontrollable CHF, arrhythmia, severe pulmonary or systemic hypertension, severe GI involvement, hepatic impairment, serum creatinine of greater than 2.0, active infection, severe diabetes, unstable atherosclerotic cardiovascular disease, malignancy, HIV, or severe peripheral vascular disease. History of pancreatitis. Prolonged QTc interval defined as a QTc > 450 msec Patients requiring the ongoing use of medications that are antiarrhythmics (including, but not limited to amiodarone, disopyramide, procainamide, quinidine and sotalol) or that prolong the QTc interval (including, but not limited to chloroquine, halofantrine, clarithromycin, haloperidol, methadone, moxifloxacin, bepridil and pimozide) will be excluded. Patients requiring the ongoing use of medications that are potent inhibitors or inducers of CYP3A4. A positive pregnancy test at entry into this study. Men and women with reproductive potential will be required to use effective means of contraception through the course of the study. Participation in another clinical research study involving the evaluation of another investigational drug within ninety days of entry into this study. The presence of severe lung disease as defined by a diffusion capacity of less than 30% of predicted.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nilotinib 400 mg twice daily<br> | Drug: Nilotinib (Tasigna)<br>* Patients will be treated with Nilotinib 400 mg two times a day for 6 months.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability |  | 6 Months and 12 months treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of Modified Rodnan Skin Score Reported as a Mean (Units Equals Number of Points) | Efficacy of Nilotinib in patients with systemic sclerosis, as defined by an improvement in the Modified Rodnan Skin Score (MRSS) The Modified Rodnan Skin Score (MRSS) measures dermal skin thickness through the examination of 17 body areas: fingers, hands, forearms, arms, feet, legs, and thighs (in pairs), and face, chest, and abdomen. The skin score is evaluated by manual palpation in each of these areas. The skin score is 0 for uninvolved skin, 1 for mild thickening, 2 for moderate thickening, and 3 for severe thickening (hidebound skin). The total skin score is the sum of the skin scores of the individual areas where the minimum score is 0 and the maximum score is 51. A higher score indicates greater severity of disease. | 6 Months of treatment | 
| Efficacy of Nilotinib in Patients With Systemic Sclerosis, as Defined by an Improvement in the Modified Rodnan Skin Score | Improvement in Modified Rodnan skin score reported as a mean (units equals number of points). The Modified Rodnan Skin Score (MRSS) measures dermal skin thickness through the examination of 17 body areas: fingers, hands, forearms, arms, feet, legs, and thighs (in pairs), and face, chest, and abdomen. In each of these areas, the skin score is evaluated by manual palpation. The skin score is 0 for uninvolved skin, 1 for mild thickening, 2 for moderate thickening, and 3 for severe thickening (hidebound skin). The total skin score is the sum of the skin scores of the individual areas. The minimum score is 0 and the maximum score is 51. A higher score indicates greater severity of disease. | 12 months treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic Sclerosis