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

Primary Purpose

Sarcoidosis, Pulmonary, Sarcoidosis Lung, Sarcoidosis

Status

Completed

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Tofacitinib 5mg Oral Tablet [Xeljanz] 16 week trial

Spirometry

RNA Sequencing

Laboratory testing

Corticosteroid

Tofacitinib 5mg [Xeljanz] 1 year open-label extension

About this trial

This is an interventional treatment trial for Sarcoidosis, Pulmonary focused on measuring Sarcoidosis, Corticosteroid dependent sarcoidosis

Eligibility Criteria

18 Years - 89 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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).

Sites / Locations

Oregon Health & Science University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Open-label treatment

Arm Description

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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.

Full Information

NCT ID

NCT03793439

First Posted

January 2, 2019

Last Updated

December 3, 2021

Sponsor

Oregon Health and Science University

Collaborators

Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT03793439

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

December 2021

Overall Recruitment Status

Completed

Study Start Date

May 15, 2019 (Actual)

Primary Completion Date

June 24, 2020 (Actual)

Study Completion Date

June 24, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Oregon Health and Science University

Collaborators

Pfizer

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Sarcoidosis, Pulmonary, Sarcoidosis Lung, Sarcoidosis

Keywords

Sarcoidosis, Corticosteroid dependent sarcoidosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Model Description

Open-label, interventional, proof of concept, hypothesis-generating study

Masking

None (Open Label)

Allocation

N/A

Enrollment

5 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Open-label treatment

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Tofacitinib 5mg Oral Tablet [Xeljanz] 16 week trial

Other Intervention Name(s)

Xeljanz, tofacitinib

Intervention Description

Tofacitinib 5mg oral table twice daily for 16 weeks

Intervention Type

Diagnostic Test

Intervention Name(s)

Spirometry

Other Intervention Name(s)

Pulmonary function test

Intervention Description

Spirometry testing at baseline, week 4, week 8, week 12, and week 16

Intervention Type

Genetic

Intervention Name(s)

RNA Sequencing

Intervention Description

RNA sequencing test at baseline and week 16

Intervention Type

Diagnostic Test

Intervention Name(s)

Laboratory testing

Other Intervention Name(s)

Blood work

Intervention Description

Laboratory testing at baseline and weeks 2, 4, 8, 12 and 16

Intervention Type

Drug

Intervention Name(s)

Corticosteroid

Other Intervention Name(s)

Corticosteroid taper, Prednisone taper, Steroid taper

Intervention Description

Taper corticosteroids starting at week 4

Intervention Type

Drug

Intervention Name(s)

Tofacitinib 5mg [Xeljanz] 1 year open-label extension

Other Intervention Name(s)

tofacitinib, Xeljanz

Intervention Description

After 16 weeks, subjects who meet the primary end-point will be permitted an optional one year open-label extension.

Primary Outcome Measure Information:

Title

Number of Participants With 50% Reduction in Corticosteroid Requirement

Description

Time Frame

16 weeks

Secondary Outcome Measure Information:

Title

Number of Participants With Significantly Decreased Expression of STAT1 Mediated Genes as Determined by RNA Sequencing

Description

Time Frame

16 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

89 Years

Accepts Healthy Volunteers

Eligibility Criteria

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).

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jim Rosenbaum, MD

Organizational Affiliation

Oregon Health and Science University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Oregon Health & Science University

City

Portland

State/Province

Oregon

ZIP/Postal Code

97239

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

De-identified individual participant data for all primary and secondary outcomes will be made available.

IPD Sharing Time Frame

January 1, 2022 until December 31, 2023

IPD Sharing Access Criteria

Email friedmam@ohsu.edu

Citations:

PubMed Identifier

25880323

Citation

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.

Results Reference

background

PubMed Identifier

33825964

Citation

Friedman MA, Le B, Stevens J, Desmarais J, Seifer D, Ogle K, Choi D, Harrington CA, Jackson P, Rosenbaum JT. Tofacitinib as a Steroid-Sparing Therapy in Pulmonary Sarcoidosis, an Open-Label Prospective Proof-of-Concept Study. Lung. 2021 Apr;199(2):147-153. doi: 10.1007/s00408-021-00436-8. Epub 2021 Apr 7.

Results Reference

derived

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

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