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

Phase 1

Completed

Conditions: Sarcoidosis
Sarcoidosis, Pulmonary
Sarcoidosis Lung

Interventions: 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

Registration Number: NCT03793439

Lead Sponsor: Oregon Health and Science University

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 5

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).

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Open-label treatment	Tofacitinib 5mg [Xeljanz] 1 year open-label extension	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.
Open-label treatment	Tofacitinib 5mg Oral Tablet [Xeljanz] 16 week trial	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.
Open-label treatment	RNA Sequencing	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.
Open-label treatment	Corticosteroid	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.
Open-label treatment	Spirometry	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.
Open-label treatment	Laboratory testing	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With 50% Reduction in Corticosteroid Requirement	16 weeks	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

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Significantly Decreased Expression of STAT1 Mediated Genes as Determined by RNA Sequencing	16 weeks	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.