Trial of Rituximab for Graves' Ophthalmopathy

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase 2/3 Study of Rituximab for Graves' Ophthalmopathy

Conditions
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Thyroid-associated Ophthalmopathy

Intervention / Treatment
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* Drug: Rituximab
* Drug: Saline
* Drug: Methylprednisolone


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Rituximab<br>Rituximab 1000 mg IV twice at 2-week intervals, each preceded by Methylprednisolone 100 mg IV as premedication to the rituximab infusion. | Drug: Rituximab<br>* Subjects will receive 2 infusions of rituximab (1000 mg IV), two weeks apart.<br>* Other names: MabThera;Drug: Methylprednisolone<br>* Subjects will receive methylprednisolone 100 mg IV as premedication to the rituximab infusion.<br>* Other names: Solu-Medrol;|
| Placebo Comparator: Placebo<br>Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV. | Drug: Saline<br>* Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Clinical Activity Score (CAS) | The clinical activity score (CAS), for Grave's ophthalmopathy has become a widely accepted tool to assess disease activity and help decide the management of the condition. The CAS, which is based on classical signs of inflammation (pain, redness, and swelling), consists of 7 equally weighted items. The total CAS (as used in this study) may range from 0 to 7. The higher the CAS, the greater degree of inflammation is present. A drop in CAS of 2 or more points suggests an improvement in the inflammatory components of the disease. A CAS ≥3 implies active disease. | baseline, 6 months after the first infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Failure Rate | The failure rate was defined as a composite variable of CAS decrease of < 2 points or need for additional therapy (excluding cosmetic surgery) for the eye disease. | 6 months after first infusion, 12 months after first infusion | 
| Change in Disease Severity | Disease severity was measured by the NOSPECS Score. This classification scheme of the eye changes in thyroid eye disease was introduced by the American Thyroid Association. It separates patients into seven classes of disease (class 0-6), with 0 being no signs or symptoms and 6 being sight loss. (The acronym is 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) ). | baseline, 6 months after first infusion | 
| Change in Proptosis | Eye proptosis is a condition resulting in forward displacement of the globe from its normal position within the orbit. It is measured by computed tomography. Improvement in proptosis was defined as a decrease in proptosis by ≥2 mm. | baseline, 12 months after first infusion | 
| Change in Lid Fissure | The palpebral fissure is the elliptic space between the medial and lateral canthi of the two open eye lids. In adults, this measures about 10mm vertically and 30mm horizontally. The fissure may be increased in vertical height in Graves' disease. Improvement was defined as a decrease in lid aperture width by ≥3 mm. | baseline, 6 months after first infusion | 
| Change in Extraocular Motility | Change extraocular motility was assessed using the Gorman diplopia score. Diplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally (i.e., both vertically and horizontally) in relation to each other. It is usually the result of impaired function of the extraocular muscles, where both eyes are still functional but they cannot converge to target the desired object. The Gorman diplopia score includes four categories: 1) no diplopia (absent), 2) diplopia when the patient is tired or awakening (intermittent), 3) diplopia at extremes of gaze (inconstant), and 4) continuous diplopia in the primary or reading position (constant). | baseline, 6 months after first infusion, 12 months after first infusion | 
| Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | Quality of life (QoL) was measured by the SF-12 questionnaire. The SF-12 is a multipurpose short form survey with 12 questions, all selected from the SF-36 Health Survey. Physical and Mental Health Composite Scores are computed (combined, scored, and weighted) using the scores of the 12 questions and range from 0 to 100, where a zero score indicates the lowest level of health measured by the scales and 100 indicates the highest level of health. Improvement was defined as a change of ≥ 6 points. | baseline, 6 months after first infusion, 12 months after first infusion | 
| Failure Rate at One Year | The failure rate was defined as a composite variable of CAS decrease of < 2 points or need for additional therapy (excluding cosmetic surgery) for the eye disease. | one year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thyroid-associated ophthalmopathy, Rituximab, Proptosis