IRB Number:

06-006130

Trial Status:

Open for Enrollment

Phase: II

Why is this study being done?

The long term objective of our work is to better understand the pathogenesis of Graves' ophthalmopathy (GO) in order to aid in the development of new approaches to treatment or prevention of this disease. The goal of the laboratory investigations in this proposal is to determine mechanisms involved in the stimulation of adipogenesis by thyrotropin receptor (TSHR)-directed autoantibodies (TRAb) in GO orbital preadipocytes. The translational goal is to determine whether rituximab, an agent that blocks the activation and differentiation of B cells, confers therapeutic benefit in a pilot study of patients with GO. We have shown that adipogenesis is enhanced in orbital tissues from GO patients, and that TRAb act to stimulate fat cell development in GO orbital preadipocytes. Further, we have demonstrated elevated expression of soluble frizzled-related protein-1 (sFRP-1) in patients' orbital tissue specimens, and present evidence that TRAb enhance expression of this protein in their orbital preadipocytes. sFRP-1 is an inhibitor of Wnt signaling that acts in preadipocytes to reverse Wnt-induced inhibition of adipogenesis, thereby enhancing fat cell development. Analogous to TRAb activating thyroidal TSHR and stimulating over-production of thyroid hormone in Graves' disease, we postulate that these autoantibodies activate TSHR on orbital preadipocytes to stimulate adipogenesis in GO. The 3 specific aims of this proposal are to test the hypotheses that: 1) TRAb-induced adipogenesis is mediated via inhibition of Wnt signaling, and that IgG from GO patients function similarly; 2) GO orbital preadipocytes differ from preadipocytes from other sites in their responses to TRAb; and 3) Rituximab is effective in the treatment of patients with severe, active GO. We will enroll 30 patients in a randomized, prospective, double-blind clinical trial to determine effects of this agent on clinical activity score, specific quantitative ocular parameters, and health-related quality of life. We believe that our program represents a novel, integrated, translational approach to the study of GO. Our studies will yield information concerning mechanisms involved in disease development, and will determine the effectiveness of a novel approach to therapy.

Who is Eligible to Participate in the Study?

Inclusion Criteria: males and females, ages 18 - 75 yrs, smokers and non smokers, euthyroid for at least 6-8 weeks (defined by normal free thyroid hormone levels, with or without thyroxine therapy), affected by active ophthalmopathy (clinical activity score ≥4/10 or ≥4/7) of moderate- severe degree, as defined by NOSPECS score, and no immediate need for decompression surgery. Previous steroid treatment is acceptable, if discontinued at least 4 weeks before enrollment.

Exclusion Criteria: contraindications to therapy with rituximab including HIV, Hepatitis B, hepatitis C,denied consent to HIV or hepatitis testing, inactive or mild GO, previous orbital radiotherapy, refusal of treatment, absolute neutrophil count < 1.5 X 109/L. Patients with known allergy to difenhyidramine.

Minimum Age:

18

Maximum Age:

75

What is Involved With this Study?

Thirty patients (both sexes, 18-75 yrs) with clinical activity score (CAS) of ≥4 and moderate to severe disease severity, as defined by NOSPECS score, will be recruited. Fifteen patients will receive RTX (1000 mg IV twice at 2-week intervals) and 15 patients will receive 2 saline infusions. All patients will be treated with acetaminophen and diphenhydramine before the infusion. Glucocorticoids (methylprednisolone 100 mg) or saline will also be administered IV as premedication to the rituximab and placebo arm respectively, in a blinded fashion but matching the randomization, to decrease the rate of infusion-associated reactions. All antihypertensive medications will be held for the 12 hours prior to and during the infusion. Patients will be assessed at weeks 8, 16, 24 and 52 for eye disease severity, CAS, TSH, fT4, fT3, TRAB, TPO and C19+B cell count. CT scan of the orbits will be obtained at baseline and week 52 for orbital volume measurements and proptosis. Thyroid ultrasound will be obtained at baseline, week 24 and week 52 for thyroid volume measurements and color Doppler flow assessment. The primary end point will be a reduction CAS of ≥ 2 points, or below CAS 3, or CAS will be assessed as a continuum. Secondary endpoints will include failure rate at 52 weeks, with failure defined as need for additional therapy (excluding cosmetic surgery) for the eye disease; A 52 weeks composite of decrease of CAS ≥ 2 points and no need for additional therapy for the eye disease versus either CAS decrease of < 2 points or need for additional therapy; decreases in disease severity by ≥2 NOSPECS classes, proptosis by ≥2 mm, lid aperture width by ≥3 mm, motility of ≥8 degrees, and improvement in a GO-specific quality-of-life scale of ≥ 6 points.

How long will the Study run?

52 Weeks

Primary Investigator

Who can I Contact for Additional Information on this Trial?

Jodi Bates, Study Coordinator: bates.jodi@mayo.edu, pager: 127-09164, phone: 507-284-3838

Dr. Marius Stan, Co-Investigator: stan.marius@mayo.edu, pager: 4-7887

What is/are the Locations of this Clinical Trial?

• Rochester, MN

Last updated: 03/31/2008