Tofacitinib for Glucocorticoid-Resistant Moderate-to-Severe Thyroid Eye Disease (TOFA-GO)

April 28, 2026 updated by: The First Affiliated Hospital of Xiamen University

A Single-Arm, Open-Label, Exploratory Study of Tofacitinib in Patients With Glucocorticoid-Resistant or Intolerant Moderate-to-Severe Active Thyroid Eye Disease

Thyroid Eye Disease (TED), also known as Graves' orbitopathy, is an autoimmune condition that causes inflammation and tissue expansion behind the eyes, leading to bulging eyes (proptosis), double vision, and pain. Currently, intravenous glucocorticoids (steroids) are the standard first-line treatment. However, approximately 20-30% of patients do not respond to steroids, or cannot tolerate their side effects.

This study aims to evaluate the safety and efficacy of Tofacitinib, an oral medication known as a Janus kinase (JAK) inhibitor, as a rescue therapy for these difficult-to-treat cases. Tofacitinib works by blocking specific signaling pathways (JAK-STAT) that drive inflammation and fibrosis in the eye socket. In this study, patients with moderate-to-severe active TED who are resistant to or intolerant of steroids will receive Tofacitinib tablets (5 mg twice daily) for 24 weeks. The researchers will assess whether the treatment can effectively reduce eye bulging and improve clinical activity scores.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Thyroid Eye Disease (TED) involves complex pathogenesis where orbital fibroblasts are activated by autoantibodies targeting the TSH receptor (TSHR) and the Insulin-like Growth Factor-1 receptor (IGF-1R). Current evidence suggests that TSHR and IGF-1R form a physical and functional complex that activates downstream signaling cascades, prominently the Janus Kinase/Signal Transducer and Activator of Transcription (JAK-STAT) pathway. The activation of STAT3, in particular, is a critical driver of hyaluronan synthesis, adipogenesis (fat expansion), and inflammation within the orbital tissue.

While intravenous glucocorticoids (IVGC) are the standard first-line treatment, they primarily exert broad anti-inflammatory effects and may fail to adequately suppress the tissue remodeling (adipogenesis and fibrosis) driven by these specific signaling pathways. Consequently, a significant proportion of patients become "steroid-resistant."

This study proposes the use of Tofacitinib, a small-molecule JAK inhibitor, as a targeted rescue therapy. By inhibiting the JAK-STAT pathway, Tofacitinib is hypothesized to suppress both the inflammatory cytokine release and the orbital tissue remodeling that persists despite steroid treatment.

Participants will enter a 24-week treatment phase receiving oral Tofacitinib (5 mg twice daily). Clinical assessments will be performed at Baseline, Week 4, 12, 24, and a follow-up visit at Week 36. Key exploratory components of this study include: 1. Quantitative Orbital Imaging: Use of Orbital MRI to objectively measure changes in extraocular muscle volume and orbital fat volume to distinguish between anti-inflammatory and anti-remodeling effects. 2. Durability of Response: A 12-week post-treatment observation period (Weeks 24-36) to monitor for disease relapse or "rebound" phenomena after drug cessation. 3. Safety in Comorbidities: Close monitoring of coagulation profiles and lipid levels, given the known safety profile of JAK inhibitors, specifically in this population with potential metabolic comorbidities.

Study Type

Interventional

Enrollment (Estimated)

8

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

  • Name: Fangsen Xiao, MD
  • Phone Number: +86-592-2137710
  • Email: xfs888@163.com

Study Contact Backup

Study Locations

  • China
    • Fujian
      • Xiamen, Fujian, China, 361003
        • Recruiting
        • The First Affiliated Hospital of Xiamen University
        • Contact:
        • Contact:
        • Principal Investigator:
          • Fangsen Xiao, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. Age and Gender: Male or female participants aged 18 to 75 years (inclusive).
  2. Diagnosis: Clinical diagnosis of Graves' orbitopathy (GO) consistent with EUGOGO criteria.
  3. Severity: Moderate-to-severe GO as defined by EUGOGO guidelines (impact on daily life, but not sight-threatening).
  4. Activity: Active disease, defined as a Clinical Activity Score (CAS) >=3 points (on the 7-point scale).
  5. Refractory Status (Must meet ONE of the following):Glucocorticoid-Resistant: Failure to respond (no significant improvement in proptosis or CAS) after receiving a cumulative dose of at least 3g of intravenous methylprednisolone (or equivalent).Glucocorticoid-Intolerant: Documented contraindications to high-dose systemic glucocorticoids (e.g., uncontrolled diabetes mellitus, severe osteoporosis, glaucoma, severe psychiatric disorders) or history of severe adverse events leading to discontinuation.
  6. Thyroid Function: Euthyroid or mild hypothyroidism/hyperthyroidism maintained on stable antithyroid drugs or thyroxine replacement therapy for at least 4 weeks prior to baseline.
  7. Contraception: Women of childbearing potential must agree to use effective contraception during the study period and for at least 4 weeks after the last dose of the study drug.
  8. Consent: Willing and able to provide written informed consent and comply with study procedures.

Exclusion Criteria:

  • 1.Sight-Threatening Disease: Presence of Dysthyroid Optic Neuropathy (DON) or severe corneal breakdown requiring immediate surgical intervention.

    2.Chronic/Inactive Disease: Fibrotic or burnout stage of GO with a Clinical Activity Score (CAS) < 3.

    3.Prior Orbital Treatment:Orbital radiotherapy at any time.Orbital surgical decompression at any time.Strabismus surgery or eyelid surgery within 3 months prior to baseline.

    4.Concomitant Immunomodulation: Use of other biologic agents (e.g., Teprotumumab, Rituximab, Tocilizumab) within 3 months prior to baseline.

    5.Active Infection Risk (Critical for JAK Inhibitors):Active tuberculosis (TB) or untreated latent TB.Active or chronic Hepatitis B or Hepatitis C infection.Human Immunodeficiency Virus (HIV) infection.History of disseminated herpes zoster or herpes simplex.Any severe active infection requiring hospitalization or IV antibiotics within 4 weeks of baseline.

    6.Thrombosis Risk: History of venous thromboembolism (VTE), including deep vein thrombosis (DVT) or pulmonary embolism (PE), or known coagulation disorders.

    8.Malignancy: History of any malignancy within the past 5 years (except adequately treated basal cell or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix).

    9.Laboratory Abnormalities:Absolute Neutrophil Count (ANC) < 1.0 *10^9/L and/or Absolute Lymphocyte Count (ALC) < 0.5 *10^9/L and /or Hemoglobin < 90 g/L and/or AST or ALT > 2* Upper Limit of Normal (ULN) and/or Estimated Glomerular Filtration Rate (eGFR) < 60 mL/min/1.73 m²

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Tofacitinib Treatment Group
Participants in this arm will receive oral Tofacitinib Citrate (5 mg) twice daily (BID) for a total treatment duration of 24 weeks. Following the 24-week treatment period, participants will undergo a 12-week drug-withdrawal observation phase to monitor for disease relapse and safety.
Drug: Tofacitinib
5 mg tablet administered orally twice daily (BID) for a continuous period of 24 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Response Rate (ORR)
Time Frame: Week12，24
Percentage of participants classified as responders in the study eye. A responder is defined as a patient who achieves at least one of the following criteria without deterioration in the fellow eye: (1) Reduction in proptosis>=2 mm; (2) Reduction in Clinical Activity Score (CAS) >= 2 points (on a 7-point scale).
Week12，24

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Proptosis
Time Frame: Baseline, Week 4, 12, 24, and 36
Mean change in proptosis from baseline in the study eye, measured by Hertel exophthalmometer in millimeters (mm).
Baseline, Week 4, 12, 24, and 36
Change in Clinical Activity Score (CAS)
Time Frame: Baseline, Week 4, 12, 24, and 36
Mean change in Clinical Activity Score (CAS) from baseline. CAS is assessed on a 7-point scale (1 point for each: spontaneous retrobulbar pain, pain on gaze, eyelid erythema, eyelid swelling, conjunctival injection, chemosis, inflammation of caruncle/plica), where higher scores indicate more active inflammation.
Baseline, Week 4, 12, 24, and 36
Diplopia Response
Time Frame: 12W,24W
ercentage of participants with improvement in diplopia. Improvement is defined as a reduction of at least one grade in the Gorman diplopia score (Grades: absent, intermittent, inconstant, constant)
12W,24W
Change in Graves' Orbitopathy Quality of Life (GO-QOL) Score
Time Frame: Baseline and Week4，12，24，36
Mean change in the Graves' Orbitopathy Quality of Life (GO-QOL) questionnaire score from baseline. The GO-QOL measures two subscales: visual functioning and appearance. For each subscale, the minimum score is 0 and the maximum score is 100. Higher scores indicate a better quality of life.
Baseline and Week4，12，24，36
Incidence of Adverse Events
Time Frame: From baseline through Week 36
Number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0, including specific monitoring for infections, herpes zoster, venous thromboembolism, and lipid profile alterations.
From baseline through Week 36

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The First Affiliated Hospital of Xiamen University

Investigators

  • Principal Investigator: Fangsen Xiao, MD, The First Affiliated Hospital of Xiamen University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 24, 2026

Primary Completion (Estimated)

December 30, 2027

Study Completion (Estimated)

December 30, 2027

Study Registration Dates

First Submitted

April 14, 2026

First Submitted That Met QC Criteria

April 21, 2026

First Posted (Actual)

April 23, 2026

Study Record Updates

Last Update Posted (Actual)

April 29, 2026

Last Update Submitted That Met QC Criteria

April 28, 2026

Last Verified

January 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • XMFHIIT-2026SL001

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

IPD will not be shared in accordance with applicable data privacy laws and institutional ethics requirements. The informed consent obtained from participants did not authorize external data sharing.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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