Clinical trial NCT00595335: Trial of Rituximab for Graves' Ophthalmopathy
Official title: Phase 2/3 Study of Rituximab for Graves' Ophthalmopathy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Thyroid-associated Ophthalmopathy
Keywords: Thyroid-associated ophthalmopathy
Rituximab
Proptosis
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: National Center for Research Resources (NCRR)
First posted: 2008-01-16
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is being done to investigate the effects (good and bad) of Rituximab for the treatment of an autoimmune eye disease called Graves' ophthalmopathy. This disease has proven to be difficult to treat. Rituximab is a monoclonal antibody that depletes a line of cells involved in the autoimmune response. The study hypotheses is that rituximab is effective in the treatment of patients with moderate to severe active Graves' ophthalmopathy.

Detailed description: Laboratory evidence suggests that autoantibodies targeting the thyrotropin receptor are directly involved in the pathogenesis of Graves' ophthalmopathy (GO). This double-blind, randomized, controlled study will determine whether rituximab, an anti-B-lymphocyte antigen (CD20) monoclonal antibody that induces transient B-cell depletion, is an effective treatment for moderate to severe, active GO.

Before any treatment is given, careful eye and thyroid physical examinations will be performed and the patients will have several thyroid blood tests, a test to count the white cells in the blood, and a CT scan of the head and eyes. A close-up photograph of the face will be taken and patients will be given a short questionnaire about how their eyes are feeling and how the eye disease is affecting their quality of life.

Each study subject will receive either 2 infusions of rituximab (each 1000 mg; given 2 weeks apart) or 2 intravenous infusions of saline. 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 return 2 weeks after the first intravenous infusion in order to receive the second infusion.

Patients will be assessed at weeks 8, 16, 24 and 52 for eye disease severity, CAS, thyroid stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), thyroid autoantibodies (TRAB), thyroid peroxidase (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.

Data analysis - Continuous variables were compared between the two treatment groups using t test or the Wilcoxon rank sum test, while categorical variables were analyzed using the chi-square /Fisher exact test. Non-parametric methods were used throughout where normality and chi-squared assumptions did not hold. General linear models were used to access treatment effect on change in CAS between baseline and 24 or 52 weeks. Patients who discontinued the trial prior to week 52 were evaluated before discontinuation and those data were carried forward to either 24 weeks (for the 5 patients who discontinued prior to or at week 24) or 52 weeks (for the single patient discontinued from the trial after 24 weeks) as the final evaluation for that patient. A p-value \< 0.05 was considered significant.

Eligibility criteria: Inclusion Criteria:

* Patients with clinical activity score (CAS) of ≥4 and moderate to severe disease severity, as defined by thyroid eye disease severity scale based on the first letter of the defining characteristic of each class, the classification is known as: 'no signs or symptoms; only signs; soft tissue; proptosis; extraocular muscle; cornea; sight loss' (NOSPECS) score
* Euthyroid for at least 6-8 weeks
* No immediate need for decompression surgery
* With disease progression over the previous 1-2 months or without evident improvement in the prior 6 months.

Exclusion Criteria:

* Corticosteroid use in the preceding 4 weeks
* HIV, hepatitis C or hepatitis B infections
* Denied consent for HIV or hepatitis testing
* Mild or inactive Graves' ophthalmopathy
* Orbital radiotherapy within 18 months or orbital surgery within the past year
* Absolute neutrophil count \< 1,500/mm\^3
* Pregnant or nursing patients
* Coronary artery disease, congestive heart failure, significant arrhythmias, significant infection or immunodeficiency, other serious illnesses

Primary outcomes:
measure: Change in Clinical Activity Score (CAS)
timeFrame: baseline, 6 months after the first infusion
Secondary outcomes:
measure: Failure Rate
timeFrame: 6 months after first infusion, 12 months after first infusion
measure: Change in Disease Severity
timeFrame: baseline, 6 months after first infusion
measure: Change in Proptosis
timeFrame: baseline, 12 months after first infusion
measure: Change in Lid Fissure
timeFrame: baseline, 6 months after first infusion
measure: Change in Extraocular Motility
timeFrame: baseline, 6 months after first infusion, 12 months after first infusion
measure: Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey
timeFrame: baseline, 6 months after first infusion, 12 months after first infusion
measure: Failure Rate at One Year
timeFrame: one year
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Mayo Clinic
name: Rebecca S Bahn, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley EA, Bahn RS. Randomized controlled trial of rituximab in patients with Graves' orbitopathy. J Clin Endocrinol Metab. 2015 Feb;100(2):432-41. doi: 10.1210/jc.2014-2572. Epub 2014 Oct 24.