Safety of Tofacitinib, an Oral Janus Kinase Inhibitor, in Primary Sjogren's Syndrome

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:

• Medical and dental history
• Physical exam
• Medicine review
• Electrocardiogram to test the heart s electrical activity (Participants will lay on a table. Sticky pads will be placed on their body.)
• Eye exam and test for dry eyes
• Oral, head, and neck exams
• Plaque collection (Dental plaques and tongue and mucosal scrapings will be collected using a small tongue depressor.)
• Salivary gland ultrasound
• Blood and urine tests
• Minor salivary gland biopsy (The lower lip will be numbed. Several tiny salivary glands will be removed through a small incision.)
• Saliva collection
• Disease assessment.

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 Overview

• Status: Recruiting
• Conditions: Sjogren's Syndrome
• Intervention / Treatment: Other: Placebo; Drug: tofacitinib

Detailed Description

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:

• To assess clinical improvement after treatment with Tofacitinib as measured by changes in the European League Against Rheumatism (EULAR) Sjogren's syndrome Disease Activity Index (ESSDAI) and no worsening on the Physician s Global assessment Scale (PGA).
• To demonstrate that treatment with Tofacitinib is effective clinically and biologically in SS individuals with mild to moderate disease.
• To investigate the effects of Tofacitinib on systemic biomarkers of SS as measures biological effects that can be used as outcome measures to power a larger Clinical Trial.

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:

• Changes in the ESSDAI score between Baseline and Day 168 (end of treatment)
• Changes in the Physician's Global Assessment (PGA) scores between baseline and study day 168.

• Study Type: Interventional
• Enrollment (Estimated): 76
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Blake M Warner, D.D.S.; Phone Number: (301) 500-8063; Email: blake.warner@nih.gov
• Study Contact Backup: Name: Sasha D Clary; Phone Number: (301) 827-5031; Email: sasha.clary@nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center
      • Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR); Phone Number: TTY8664111010 800-411-1222; Email: prpl@cc.nih.gov

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

Adult primary SS participants with mild-to-moderate disease activity will be eligible for this study. Enrolled participants can be na(SqrRoot) ve 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:

1. Ability of participant to understand and the willingness to sign a written informed consent document.
2. Participation and enrollment in companion protocol, 15-D-0051, Characterization of Diseases with Salivary Gland Involvement.
3. Stated willingness to comply with all study procedures and availability for the duration of the study
4. Male or female, aged between 18-75 years
5. In good general health as evidenced by medical history
6. Meets the 2002 American European Consensus Group classification criteria for primary Sjogren's Syndrome or 2016 American College of Rheumatology/European League against Rheumatism Classification Criteria (ACR-EULAR) with mild to moderate disease activity defined as ESSDAI between 0 to 13 at the screening visit and >0 ml/min/gland stimulated saliva flow.
7. Ability to take oral medication and be willing to adhere to the study intervention regimen
8. If on glucocorticoids, the dose must be less than 10 mg daily and stable for the 4 weeks (28 days) prior to screening visit.
9. If on hydroxychloroquine or other antimalarials such as chloroquine or quinacrine, the dose must have been stable for the 12 weeks (96 days) prior to screening visit. The maximum allowed dose is hydroxychloroquine up to 400 mg/day or 6.5 mg/kg/day if more than 400 mg/day. The maximum allowed dose for chloroquine phosphate is up to 500 mg daily and for quinacrine up to 100 mg daily.
10. Participants may be on lipid lowering medications if initiated at least 3 months prior to the screening visit and dose must be stable for 4 weeks (28 days) prior to study entry.
11. Males and females with potential for reproduction must agree to practice effective birth control measures. Females should be on adequate contraception if they are of child-bearing potential documented by a clinician, unless participants or spouse have previously undergone a sterilization procedure. Adequate birth control measures are: intrauterine device (IUD) alone or hormone implants, hormone patches, injectable, or oral contraceptives plus a barrier method (male condom, female condom or diaphragm), abstinence or a vasectomized partner.
12. Agreement to adhere to Lifestyle Considerations throughout study duration

EXCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must not meet any of the following criteria:

1. Current or prior treatment with rituximab, belimumab or any other biologic agent in the 6 months prior to screening.
2. 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.
3. Treatment with cyclophosphamide, pulse methylprednisolone or IVIG within 6 months prior to screening.
4. 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.

5. History of chronic liver disease, not including well-controlled Sjogren s-related chronic liver disease or elevated LFTs:

   • ALT or AST >= 2x upper limit of normal at screening
   • Serum unconjugated bilirubin > 2mg/dL at screening
6. Serum creatinine >1.5mg/dL.
7. 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).
8. Active urinary sediment (WBC, RBC or mixed cellular casts 1+ or more /hpf).
9. 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.
10. WBC <2500/microliter or ANC <1,000/microliter, Hgb <9.0 g/dL or platelets <70,000/microliter or absolute lymphocyte count < 500/microliter.
11. Pregnant or lactating women. Women of childbearing potential are required to have a negative pregnancy test at screening.
12. A history of drug or alcohol abuse within the 6 months prior to screening.
13. Currently receiving hemodialysis, peritoneal dialysis, or intestinal dialysis.
14. 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.
15. Active chronic infections including but not limited to HIV, Hepatitis B, Hepatitis C, and BK viremia at screening visit.
16. 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.
17. 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.
18. History of opportunistic infections.
19. Participants with active renal or central nervous system disease or a high activity level in any organ system (except articular) in ESSDAI^54.

20. Participants with known increased risk factors for major adverse cardiac event (MACE) including a history of:

    • Ischemic heart disease (e.g., history of acute myocardial infarction)
    • Heart failure
    • Cardiomyopathy
    • Severe valvular heart disease
    • Significant arrhythmias
    • Chronic renal failure
    • Cerebrovascular accident or transient ischemic attack
    • Uncontrolled diabetes mellitus
    • Uncontrolled hypertension
    • Current smokers or former smokers with less than 3 years since complete cessation and/or >20 pack-years of smoking history.
21. 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.
22. Known history of arterial or venous thrombosis or at high risk for clotting disorder
23. Psychiatric illness or history of medical non-compliance that the study team feels will make the patient unlikely to complete the study
24. Uncontrolled thyroid disease as per PI or medically responsible investigator.
25. Known allergic reactions to Tofacitinib or its components
26. Treatment with another investigational drug/intervention within six months except for COVID-19 vaccines or therapies that have been granted an FDA emergency authorization.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo group; Receiving placebo	Other: Placebo; white, round, film-coated tablet
Experimental: Subjects with SS; Receiving tofacidinib	Drug: tofacitinib; XELJANZ(R) is the citrate salt of tofacitinib. Tofacitinib citrate is a white to off-white powder with the following chemical name: (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3-d]pyrimidin-4-ylamino) -beta-oxo-1-piperidinepropanenitrile, 2-hydroxy-1,2,3-propanetricarboxylate (1:1) It is freely soluble in water and has a molecular weight of 504.5 Daltons. XELJANZ(R) is supplied for oral administration as 5 mg tofacitinib (equivalent to 8 mg tofacitinib citrate) white round, immediate-release film-coated tablet. Each tablet of XELJANZ(R) contains the appropriate amount of XELJANZ(R) as a citrate salt and the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, HPMC 2910/Hypromellose 6cP, titanium dioxide, macrogol/PEG3350, and triacetin.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
safety and tolerability of tofacitinib	To determine the safety and tolerability of tofacitinib in subjects with SS and mild to moderate disease activity.	week 24 (end of Treatment)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ESSDAI	The ESSDAI was developed to be used as an outcome measure in clinical trials involving Sjogren s Syndrome patient cohorts and allows for assessment/scoring of major domain activity relevant to a SS population.	Week 24
changes in salivary flow rates	salivary flow rates are an objective measure of organ function. Low salivary flow is a primary feature of SS and may be used as a non-invasive measure of therapeutic intervention. Studying the effects of tofacitinib versus placebo via randomized trial provides the best opportunity to show causality and association.	week 24

Collaborators and Investigators

• Sponsor: National Institute of Dental and Craniofacial Research (NIDCR)
• Investigators: Principal Investigator: Blake M Warner, D.D.S., National Institute of Dental and Craniofacial Research (NIDCR)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2021
• Primary Completion (Estimated): September 21, 2025
• Study Completion (Estimated): September 22, 2025

Study Registration Dates

• First Submitted: August 2, 2020
• First Submitted That Met QC Criteria: August 2, 2020
• First Posted (Actual): August 4, 2020

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: April 16, 2024
• Last Verified: April 15, 2024

More Information

Terms related to this study

• Keywords: Inflammation; Safety; Xerostomia; Salivary; Dry Mouth
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Autoimmune Diseases; Eye Diseases; Disease; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Stomatognathic Diseases; Mouth Diseases; Lacrimal Apparatus Diseases; Arthritis, Rheumatoid; Xerostomia; Salivary Gland Diseases; Dry Eye Syndromes; Syndrome; Sjogren's Syndrome; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Janus Kinase Inhibitors; Tofacitinib
• Other Study ID Numbers: 200131; 20-D-0131

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: .The Study team does not have a plan or not yet known if there is a plan to make IPD available.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No