Safety of Tofacitinib, an Oral Janus Kinase Inhibitor, in Primary Sjogren's Syndrome; a Phase Ib-IIa Placebo-controlled Clinical Trial and Associated Mechanistic Studies
Safety of Tofacitinib, an Oral Janus Kinase Inhibitor, in Primary Sjogren's Syndrome; a Phase Ib-IIa Placebo-controlled Clinical Trial and Associated Mechanistic Studies
Background:
An autoimmune disease is one in which the immune system attacks a person's own body. Sjogren's syndrome (SS) is an autoimmune disease. It often involves multiple systems and organs of the body. Researchers are trying to find new, more effective and safe treatments for SS.
Objective:
To evaluate the safety and tolerance of tofacitinib in people with SS.
Eligibility:
Adults ages 18-75 with SS.
Design:
Participants will be screened on a separate protocol. They will undergo:
Participants will repeat some of the screening tests during the study.
Participants will take capsules of the study drug or a placebo by mouth for 168 days.
Participants will have tests to measure blood pressure and the speed of blood flow through the organs. They will also have a test that examines the function and reaction of the blood vessels. For these tests, they will wear blood pressure cuffs and other sensors.
Participants will complete questionnaires about their health.
Participants will have 9 study visits over 28 weeks. They may be contacted by phone between study visits.
Study Description:
As a primary objective, this study represents an innovative investigative measure of the safety and tolerability of JAK inhibition in participants with primary Sjogren's syndrome. Secondary objectives will include investigating the effects of Tofacitinib on target tissues (e.g., salivary glands), systemic inflammation, and on vascular function in SS participants. We also aim to identify biomarkers of response that may be useful as endpoints in future studies.
Objectives:
Primary Objective:
-To determine the safety and tolerability of Tofacitinib in participants with SS and mild to moderate disease activity.
Secondary Objectives:
Endpoints:
Primary Endpoint:
-Safety and tolerability will be measured by assessment of adverse events (AEs) and clinical safety laboratory tests throughout the study. Toxicity is defined as any study drug-related Grade 3 adverse event or higher (as measured by the National Cancer Institute (NCI), Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0).
Secondary Endpoints:
Preliminary assessments of clinical response will be measured by:
Adult primary SS participants with mild-to-moderate disease activity will be eligible for this study. Enrolled participants can be naïve or failed immunosuppressive therapy beyond antimalarials and glucocorticoids; to prevent bias in the cohort of participants with more recalcitrant disease. We expect that Tofacitinib is a potential second line therapy, in addition to antimalarials and glucocorticoids, depending on the participant's initial presentation and response. Women and members of minority groups, if eligible, will be included in accordance with the NIH Policy on Inclusion of Women and Minorities as Participants in Research Involving Human Participants.
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
EXCLUSION CRITERIA:
In order to be eligible to participate in this study, an individual must not meet any of the following criteria:
Current or prior treatment with rituximab, belimumab or any other biologic agent in the 6 months prior to screening.
Current treatment with methotrexate, azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus, or other less common immunomodulatory drugs such as those falling into the class of disease-modifying antirheumatic drugs (DMARDs), not otherwise specified herein. Participants previously on methotrexate, azathioprine, mycophenolate mofetil, cyclosporine or tacrolimus, or other DMARDs should have withdrawn drug for at least 8 weeks (56 days) at the time of screening.
Treatment with cyclophosphamide, pulse methylprednisolone or IVIG within 6 months prior to screening.
Current treatment with potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g., ketoconazole) or receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole) that would increase serum availability of Tofacitinib. Past treatment with the aforementioned agent is allowed if it was more than a week prior to the administration of the first dose of study medication.
History of chronic liver disease, not including well-controlled Sjogren's-related chronic liver disease or elevated liver function tests (LFT):
Serum creatinine >1.5mg/dL.
Protein to creatinine ratio of more than 1mg/dL at screening (repeated and confirmed three times or confirmed with 24 hours urine protein of more than 1000mg).
Active urinary sediment (WBC, red blood cell (RBC) or mixed cellular casts 1+ or more /hpf)).
Hypercholesterolemia: Values after 8-12 hour fasting blood specimen: total cholesterol >250 mg/dL or LDL >180 mg/dL or hypertriglyceridemia (triglyceride >300 mg/dL) within-45 days of screening visit.
WBC <2500/microliter or absolute neutrophil count (ANC) <1,000/microliter, Hgb <9.0 g/dL or platelets <70,000/microliter or absolute lymphocyte count < 500/microliter.
Pregnant or lactating women. Women of childbearing potential are required to have a negative pregnancy test at screening.
A history of drug or alcohol abuse within the 6 months prior to screening.
Currently receiving hemodialysis, peritoneal dialysis, or intestinal dialysis.
Active infection that requires the use of oral or intravenous antibiotics unresolved at least 14 days prior to the administration of the first dose of study medication.
Active chronic infections including but not limited to HIV, Hepatitis B, Hepatitis C, and BK viremia at screening visit.
Current or previous diagnosis of malignant disease, except for basal cell or squamous cell carcinoma of the skin with complete excision and clear borders or adequately treated in situ carcinoma of the cervix.
Known active tuberculosis. Participants with treated latent tuberculosis (LTB) will be eligible to participate. Participants with untreated LTB will not be excluded but will be evaluated by an infectious disease (I.D.) consultant and may become eligible for trial based on infectious disease consultant recommendations.
History of severe or systemic infection caused by common pathogens, or history of infection with pathogens that normally do not cause human disease.
Participants with active renal or central nervous system disease or a high activity level in any organ system (except articular) in ESSDAI.
Participants with known increased risk factors for major adverse cardiac event (MACE) including a history of:
Significant impairment of major organ function (lung, heart, liver, kidney) or any condition that, in the opinion of the Investigator, would jeopardize the participant's safety following exposure to the study drug.
Known history of arterial or venous thrombosis or at high risk for clotting disorder
Psychiatric illness or history of medical non-compliance that the study team feels will make the patient unlikely to complete the study
Uncontrolled thyroid disease as per PI or medically responsible investigator.
Known allergic reactions to Tofacitinib or its components
Treatment with another investigational drug/intervention within six months except for COVID-19 vaccines or therapies that have been granted an FDA emergency authorization.