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 Phase Ib-IIa Placebo-Controlled Clinical Trial and Associated Mechanistic Studies


Lead Sponsor: National Institute of Dental and Craniofacial Research (NIDCR)

Source National Institutes of Health Clinical Center (CC)
Brief Summary

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.

Detailed Description

This study represents an innovative investigative measure of the safety and tolerability of JAK inhibition in patients with primary Sjogren's Syndrome (SS). Secondary objectives will include investigating the effects of tofacitinib on target tissues (e.g., salivary glands), systemic inflammation, and on vascular function in SS subjects. We also aim to identify biomarkers of response that may be useful as endpoints in future studies.

Overall Status Not yet recruiting
Start Date November 4, 2020
Completion Date February 5, 2024
Primary Completion Date February 6, 2023
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
safety and tolerability of tofacitinib week 24 (end of Treatment)
Secondary Outcome
Measure Time Frame
changes in salivary flow rates week 24
ESSDAI Week 24
Enrollment 30

Intervention Type: Drug

Intervention Name: tofacitinib

Description: 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.

Arm Group Label: Subjects with SS

Intervention Type: Other

Intervention Name: Placebo

Description: white, round, film-coated tablet

Arm Group Label: Placebo group



- INCLUSION CRITERIA: 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 consentdocument. 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Male or female, aged between 18-75 years 4. In good general health as evidenced by medical history or diagnosed with Sjogren's syndrome with mild to moderate disease activity as defined by ESSDAI between 2 to 13 at the screening visit and >0 ml/min/gland stimulated saliva flow. 5. Ability to take oral medication and be willing to adhere to the study intervention regimen 6. 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. 7. 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. 8. 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 9. Agreement to adhere to Lifestyle Considerations throughout study duration EXCLUSION CRITERIA: An individual who meets any of the following criteria will be excluded from participation in this study: 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). Participants previously on methotrexate, azathioprine, mycophenolate mofetil, cyclosporine or tacrolimus 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. If on glucocorticoids, the dose must be <= 10 mg daily and stable for the 4 weeks (28 days) prior to screening visit. 6. Focus Score <= 1.0 at their last salivary gland biopsy 7. History of chronic liver disease or elevated LFTs: - ALT or AST >= 2x upper limit of normal at screening - Serum unconjugated bilirubin > 2mg/dL at screening 8. Serum creatinine >1.5mg/dL. 9. Protein to creatinine ratio of more than 1mg/dL repeated and confirmed three times or confirmed with 24 hours urine protein of more than 1000 mg). 10. Active urinary sediment (WBC, RBC or mixed cellular casts 1+ or more /hpf). 11. 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. 12. WBC <2500/microliter or ANC <1,000/microliter, Hgb <9.0 g/dL or platelets <70,000/microliter or absolute lymphocyte count < 500/microliter. 13. Pregnant or lactating women. Women of childbearing potential are required to have a negative pregnancy test at screening. 14. A history of drug or alcohol abuse within the 6 months prior to screening. 15. Currently receiving hemodialysis, peritoneal dialysis, or intestinal dialysis. 16. 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. 17. Active chronic infections including but not limited to HIV, Hepatitis B, Hepatitis C, and BK viremia at screening visit. 18. 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. 19. Known active tuberculosis. Participants with untreated latent tuberculosis (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. 20. History of opportunistic infections. 21. Participants with active renal or central nervous system disease or a high activity level in any organ system (except articular) in ESSDAI . 22. 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. 23. Known history of arterial or venous thrombosis or at high risk for clotting disorder 24. Psychiatric illness or history of medical non-compliance that the study team feels will make the patient unlikely to complete the study 25. Uncontrolled thyroid disease as per PI or medically responsible investigator. 26. Known allergic reactions to tofacitinib or its components 27. Treatment with another investigational drug or other intervention within six months. 28. Current smoker or tobacco use within 3 months.

Gender: All

Minimum Age: 18 Years

Maximum Age: 75 Years

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Blake M Warner, D.D.S. Principal Investigator National Institute of Dental and Craniofacial Research (NIDCR)
Overall Contact

Last Name: Caroline Webb, R.N.

Phone: (301) 451-9462

Email: [email protected]

Facility: Contact: National Institutes of Health Clinical Center For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR) 800-411-1222 TTY8664111010 [email protected]
Location Countries

United States

Verification Date

July 31, 2020

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Placebo group

Type: Placebo Comparator

Description: Receiving placebo

Label: Subjects with SS

Type: Experimental

Description: Receiving tofacidinib

Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)