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

Sponsor
Oregon Health and Science University (Other)
Overall Status
Completed
CT.gov ID
NCT03793439
Collaborator
Pfizer (Industry)
5
1
1
25.3
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Study Details

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.

Condition or Disease Intervention/Treatment Phase
  • 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
Phase 1

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
5 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Intervention Model Description:
Open-label, interventional, proof of concept, hypothesis-generating studyOpen-label, interventional, proof of concept, hypothesis-generating study
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Tofacitinib Hypothesis-generating, Pilot Study for Corticosteroid-Dependent Sarcoidosis
Actual Study Start Date :
May 15, 2019
Actual Primary Completion Date :
Jun 24, 2020
Actual Study Completion Date :
Jun 24, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Open-label treatment

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
Tofacitinib 5mg oral table twice daily for 16 weeks
Other Names:
  • Xeljanz
  • tofacitinib
  • Diagnostic Test: Spirometry
    Spirometry testing at baseline, week 4, week 8, week 12, and week 16
    Other Names:
  • Pulmonary function test
  • 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
    Other Names:
  • Blood work
  • Drug: Corticosteroid
    Taper corticosteroids starting at week 4
    Other Names:
  • Corticosteroid taper
  • Prednisone taper
  • Steroid taper
  • Drug: 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.
    Other Names:
  • tofacitinib
  • Xeljanz
  • Outcome Measures

    Primary Outcome Measures

    1. 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

    1. 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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 89 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Oregon Health & Science University Portland Oregon United States 97239

    Sponsors and Collaborators

    • Oregon Health and Science University
    • Pfizer

    Investigators

    • Principal Investigator: Jim Rosenbaum, MD, Oregon Health and Science University

    Study Documents (Full-Text)

    More Information

    Publications

    Responsible Party:
    Jim Rosenbaum, Professor of Ophthalmology, Medicine, and Cell Biology, OHSU, Oregon Health and Science University
    ClinicalTrials.gov Identifier:
    NCT03793439
    Other Study ID Numbers:
    • STUDY00017902
    First Posted:
    Jan 4, 2019
    Last Update Posted:
    Feb 18, 2022
    Last Verified:
    Dec 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Jim Rosenbaum, Professor of Ophthalmology, Medicine, and Cell Biology, OHSU, Oregon Health and Science University
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Open Label
    Arm/Group Description Tofacitinib 5 mg twice daily by mouth
    Period Title: Overall Study
    STARTED 5
    COMPLETED 3
    NOT COMPLETED 2

    Baseline Characteristics

    Arm/Group Title Open-label Treatment
    Arm/Group 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. Tofacitinib 5mg Oral Tablet [Xeljanz] 16 week trial: Tofacitinib 5mg oral table twice daily for 16 weeks Spirometry: Spirometry testing at baseline, week 4, week 8, week 12, and week 16 RNA Sequencing: RNA sequencing test at baseline and week 16 Laboratory testing: Laboratory testing at baseline and weeks 2, 4, 8, 12 and 16 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.
    Overall Participants 5
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    40.8
    Sex: Female, Male (Count of Participants)
    Female
    1
    20%
    Male
    4
    80%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    0
    0%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    1
    20%
    White
    4
    80%
    More than one race
    0
    0%
    Unknown or Not Reported
    0
    0%
    Region of Enrollment (participants) [Number]
    United States
    5
    100%

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With 50% Reduction in Corticosteroid Requirement
    Description 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
    Time Frame 16 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Open Label
    Arm/Group Description open label tofacitinib
    Measure Participants 5
    Count of Participants [Participants]
    3
    60%
    2. Secondary Outcome
    Title Number of Participants With Significantly Decreased Expression of STAT1 Mediated Genes as Determined by RNA Sequencing
    Description 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.
    Time Frame 16 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Open Label
    Arm/Group Description open label tofacitinib
    Measure Participants 2
    Count of Participants [Participants]
    0
    0%

    Adverse Events

    Time Frame Adverse event data were collected from week 0 (start of study drug) until study drug was stopped, plus 4 weeks of post-treatment follow up. This corresponded to 72 weeks for subjects who completed the study and open-label extension: study (16 weeks), open-label extension (52 weeks), and post-treatment follow up (4 weeks). Adverse event data from subjects who terminated the study early were collected until study drug was stopped + 4 weeks.
    Adverse Event Reporting Description
    Arm/Group Title Open Label
    Arm/Group Description open label tofacitinib
    All Cause Mortality
    Open Label
    Affected / at Risk (%) # Events
    Total 0/5 (0%)
    Serious Adverse Events
    Open Label
    Affected / at Risk (%) # Events
    Total 2/5 (40%)
    Nervous system disorders
    Peripheral motor neuropathy 1/5 (20%) 1
    Skin and subcutaneous tissue disorders
    Skin infection 1/5 (20%) 1
    Other (Not Including Serious) Adverse Events
    Open Label
    Affected / at Risk (%) # Events
    Total 4/5 (80%)
    Gastrointestinal disorders
    Vomiting 1/5 (20%) 1
    Diarrhea 1/5 (20%) 1
    Musculoskeletal and connective tissue disorders
    Arthralgia 2/5 (40%) 2
    Renal and urinary disorders
    Renal colic 1/5 (20%) 1
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis 1/5 (20%) 1
    Cough 1/5 (20%) 1
    Bronchial infection 1/5 (20%) 1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular 1/5 (20%) 1

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Marcia Friedman
    Organization Oregon Health & Science University
    Phone 5034948637
    Email friedmam@ohsu.edu
    Responsible Party:
    Jim Rosenbaum, Professor of Ophthalmology, Medicine, and Cell Biology, OHSU, Oregon Health and Science University
    ClinicalTrials.gov Identifier:
    NCT03793439
    Other Study ID Numbers:
    • STUDY00017902
    First Posted:
    Jan 4, 2019
    Last Update Posted:
    Feb 18, 2022
    Last Verified:
    Dec 1, 2021