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

Sarcoidosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03793439
• Other study ID #: STUDY00017902
• Status: Completed
• Phase: Phase 1
• Start date: May 15, 2019
• Est. completion date: June 24, 2021

Study information

• Verified date: December 2021
• Source: Oregon Health and Science University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 5
• Est. completion date: June 24, 2021
• Est. primary completion date: June 24, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 89 Years

Eligibility

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).

Related Conditions & MeSH terms

• Sarcoidosis
• Sarcoidosis Lung
• Sarcoidosis, Pulmonary

Intervention

Drug:
• Tofacitinib 5mg Oral Tablet [Xeljanz] 16 week trial
Tofacitinib 5mg oral table twice daily for 16 weeks

Diagnostic Test:
• Spirometry
Spirometry testing at baseline, week 4, week 8, week 12, and week 16

Genetic:
• RNA Sequencing
RNA sequencing test at baseline and week 16

Diagnostic Test:
• Laboratory testing
Laboratory testing at baseline and weeks 2, 4, 8, 12 and 16

Drug:
• Corticosteroid
Taper corticosteroids starting at week 4
• Tofacitinib 5mg [Xeljanz] 1 year open-label extension
After 16 weeks, subjects who meet the primary end-point will be permitted an optional one year open-label extension.

Locations

Country	Name	City	State
United States	Oregon Health & Science University	Portland	Oregon

Sponsors (2)

Lead Sponsor	Collaborator
Oregon Health and Science University	Pfizer

Country where clinical trial is conducted

United States, 

References & Publications (1)

Rosenbaum JT, Choi D, Wilson DJ, Grossniklaus HE, Harrington CA, Sibley CH, Dailey RA, Ng JD, Steele EA, Czyz CN, Foster JA, Tse D, Alabiad C, Dubovy S, Parekh P, Harris GJ, Kazim M, Patel P, White V, Dolman P, Korn BS, Kikkawa D, Edward DP, Alkatan H, Al-Hussain H, Yeatts RP, Selva D, Stauffer P, Planck SR. Parallel Gene Expression Changes in Sarcoidosis Involving the Lacrimal Gland, Orbital Tissue, or Blood. JAMA Ophthalmol. 2015 Jul;133(7):770-7. doi: 10.1001/jamaophthalmol.2015.0726. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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