Tofacitinib Hypothesis-generating, Pilot Study for Corticosteroid-Dependent Sarcoidosis

Study Overview
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Brief Summary
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This is a pilot study to determine whether further research is warranted to assess whether tofacitinib is an effective steroid sparing treatment for pulmonary sarcoidosis. The primary endpoint for this study is a 50% or greater reduction in corticosteroid requirement.

Detailed Description
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Primary Objectives: Objective 1: Test the hypothesis that the addition of tofacitinib will allow patients with sarcoidosis to have 50% or greater reduction in their corticosteroid requirement without a significant decrease in pulmonary function testing, and with a similar quality of life as measured by a validated questionnaire (1). Objective 2: Test the hypothesis that the addition of tofacitinib will result in significantly decreased expression of signal transducer and activator of transcription (STAT)-1 dependent gene expression. Outline: This is a 16-week open-label, interventional, proof of concept, hypothesis-generating study. All subjects will receive Tofacitinib 5mg twice daily for 16 weeks. After four weeks on Tofacitinib, the corticosteroid will be tapered per a pre-defined protocol; once a reduction of 50% has been achieved, any further taper will be per physician discretion. After 16 weeks, subjects who meet the primary end-point will be permitted an optional one year open-label extension.

Official Title
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Tofacitinib Hypothesis-generating, Pilot Study for Corticosteroid-Dependent Sarcoidosis

Conditions
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Sarcoidosis, Pulmonary, Sarcoidosis Lung, Sarcoidosis

Intervention / Treatment
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* Drug: Tofacitinib 5mg Oral Tablet [Xeljanz] 16 week trial
* Diagnostic Test: Spirometry
* Genetic: RNA Sequencing
* Diagnostic Test: Laboratory testing
* Drug: Corticosteroid
* Drug: Tofacitinib 5mg [Xeljanz] 1 year open-label extension


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meet World Association of Sarcoidosis and other Granulomatous Disorders (WASOG) definition of pulmonary sarcoid Histologically proven sarcoid Evidence of pulmonary sarcoid on chest radiograph Forced vital capacity of > 50% Require 15-30mg/day of prednisone or equivalent corticosteroid to control sarcoidosis. Stable dose of prednisone or equivalent corticosteroid for 4 weeks prior to enrollment. Exclusion Criteria: May be taking methotrexate but not other immunosuppressive or immunomodulatory treatments in the two months prior to study period. This includes but is not limited to azathioprine, cyclophosphamide, leflunomide, mycophenolate mofetil, cyclosporine, tacrolimus, and biologic medications. Patients requiring >30mg/day prednisone or equivalent. Pregnant or lactating women. Hemoglobin < 9g/dL or hematocrit < 30% White blood cell count <3.0 K/cu mm Absolute neutrophil count <1.2 K/cu mm Platelet count <100 K/cu mm Subjects with an estimated glomerular filtration rate (GFR) ≤40 ml/min Subjects with a total bilirubin, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) more than 1.5 times the upper limit of normal at screening. Severe, progressive, or uncontrolled chronic liver disease including fibrosis, cirrhosis, or recent or active hepatitis. History of any lymphoproliferative disorder such as Epstein Barr virus (EBV) related lymphoproliferative disorder, history of lymphoma, leukemia, or signs and symptoms suggest of current lymphatic disease. Current malignancy or history of malignancy, with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin, or cervical carcinoma in situ. Have or have had an opportunistic infection (e.g., herpes zoster [shingles], cytomegalovirus, Pneumocystis carinii, aspergillosis and aspergilloma, histoplasmosis, or mycobacteria other than TB) within 6 months prior to screening. Have a known infection with human immunodeficiency virus (HIV) Have current signs and symptoms of systemic lupus erythematosus, or severe, progressive, or uncontrolled renal, hepatic, hematologic, endocrine, pulmonary, cardiac (New York Heart Association class III or IV), neurologic, or cerebral diseases (with the exception of sarcoidosis).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 89 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
Interventional Model Description: Open-label, interventional, proof of concept, hypothesis-generating study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Open-label treatment<br>All subjects will receive tofacitinib 5mg twice daily from week 0 to week 16, and a corticosteroid taper starting at week 16. Participants also undergo spirometry, RNA sequence testing, and laboratory evaluations. | Drug: Tofacitinib 5mg Oral Tablet [Xeljanz] 16 week trial<br>* Tofacitinib 5mg oral table twice daily for 16 weeks<br>* Other names: tofacitinib;Diagnostic Test: Spirometry<br>* Spirometry testing at baseline, week 4, week 8, week 12, and week 16<br>* Other names: Pulmonary function test;Genetic: RNA Sequencing<br>* RNA sequencing test at baseline and week 16<br>Diagnostic Test: Laboratory testing<br>* Laboratory testing at baseline and weeks 2, 4, 8, 12 and 16<br>* Other names: Blood work;Drug: Corticosteroid<br>* Taper corticosteroids starting at week 4<br>* Other names: Steroid taper;Drug: Tofacitinib 5mg [Xeljanz] 1 year open-label extension<br>* After 16 weeks, subjects who meet the primary end-point will be permitted an optional one year open-label extension.<br>* Other names: Xeljanz;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With 50% Reduction in Corticosteroid Requirement | 50% reduction in corticosteroid requirement by week 16, without significant decline in their pulmonary function-defined as a >15% decline in forced vital capacity (FVC), forced expiratory volume at 1 second (FEV1), or diffusing capacity of lung for carbon monoxide (DLCO) relative to the baseline value | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Significantly Decreased Expression of STAT1 Mediated Genes as Determined by RNA Sequencing | Peripheral blood RNA sequencing performed before and after 16 weeks of tofacitinib treatment. Significant changes are defined as at least 1.5 fold change in the expression of STAT1-mediated genes, with a false discover rate p value of < 0.05. | 16 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sarcoidosis, Corticosteroid dependent sarcoidosis