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| ID | Type | Description | Link |
|---|---|---|---|
| R01DK077814-01 | U.S. NIH Grant/Contract | View source | |
| UL1RR024150 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) | NIH |
| National Center for Research Resources (NCRR) | NIH |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Rituximab | Experimental | Rituximab 1000 mg IV twice at 2-week intervals, each preceded by Methylprednisolone 100 mg IV as premedication to the rituximab infusion. |
|
| Placebo | Placebo Comparator | Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rituximab | Drug | Subjects will receive 2 infusions of rituximab (1000 mg IV), two weeks apart. |
|
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Rebecca S Bahn, MD | Mayo Clinic | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Mayo Clinic | Rochester | Minnesota | 55905 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 25343233 | Derived | 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. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Rituximab | Rituximab 1000 mg IV twice at 2-week intervals, each preceded by Methylprednisolone 100 mg IV as premedication to the rituximab infusion. All subjects will be treated with an acetaminophen tablet and a diphenhydramine hydrochloride tablet before the infusion. Rituximab: Subjects will receive 2 infusions of rituximab (1000 mg IV), two weeks apart. Methylprednisolone: Subjects will receive methylprednisolone 100 mg IV as premedication to the rituximab infusion. |
| FG001 | Placebo | Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV. All subjects will be treated with an acetaminophen tablet and a diphenhydramine hydrochloride tablet before the infusion. Saline: Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Baseline to Six Months |
|
| |||||||||||||||||||||
| Six Months to Twelve Months |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Rituximab | Rituximab 1000 mg IV twice at 2-week intervals, each preceded by Methylprednisolone 100 mg IV as premedication to the rituximab infusion. All subjects will be treated with an acetaminophen tablet and a diphenhydramine hydrochloride tablet before the infusion. Rituximab: Subjects will receive 2 infusions of rituximab (1000 mg IV), two weeks apart. Methylprednisolone: Subjects will receive methylprednisolone 100 mg IV as premedication to the rituximab infusion. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | Sample size was computed based on the expected drop of 2.9 and 1.5 points in the CAS score in rituximab and placebo groups. A sample size of 15 in each group will have 80% power to detect a difference in mean values of 1.4 assuming that the common standard deviation is 1.27 using a two group t-test with a 0.050 two-sided significance level. | Posted | Mean | Standard Deviation | units on a scale | baseline, 6 months after the first infusion |
|
Participants were followed for adverse events for one year after the first infusion.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Rituximab | Rituximab 1000 mg IV twice at 2-week intervals, each preceded by Methylprednisolone 100 mg IV as premedication to the rituximab infusion. All subjects will be treated with an acetaminophen tablet and a diphenhydramine hydrochloride tablet before the infusion. Rituximab: Subjects will receive 2 infusions of rituximab (1000 mg IV), two weeks apart. Methylprednisolone: Subjects will receive methylprednisolone 100 mg IV as premedication to the rituximab infusion. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dysthroid optic neuropathy | Eye disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Myalgia | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Rebecca S. Bahn | Mayo Clinic | 507-284-2462 | bahn.rebecca@mayo.edu |
Not provided
| ID | Term |
|---|---|
| D049970 | Graves Ophthalmopathy |
| D005094 | Exophthalmos |
| ID | Term |
|---|---|
| D015785 | Eye Diseases, Hereditary |
| D005128 | Eye Diseases |
| D006111 | Graves Disease |
| D009916 | Orbital Diseases |
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| ID | Term |
|---|---|
| D000069283 | Rituximab |
| D012965 | Sodium Chloride |
| D008775 | Methylprednisolone |
| D008776 | Methylprednisolone Hemisuccinate |
| ID | Term |
|---|---|
| D058846 | Antibodies, Monoclonal, Murine-Derived |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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| Saline | Drug | Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV. |
|
| Methylprednisolone | Drug | Subjects will receive methylprednisolone 100 mg IV as premedication to the rituximab infusion. |
|
|
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 |
| Adverse Event |
|
| NOT COMPLETED |
|
|
| BG001 | Placebo | Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV. All subjects will be treated with an acetaminophen tablet and a diphenhydramine hydrochloride tablet before the infusion. Saline: Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Clinical Activity Score | 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. | Mean | Standard Deviation | units on a scale |
|
| OG000 |
| Rituximab |
Rituximab 1000 mg IV twice at 2-week intervals, each preceded by Methylprednisolone 100 mg IV as premedication to the rituximab infusion. All subjects will be treated with an acetaminophen tablet and a diphenhydramine hydrochloride tablet before the infusion. Rituximab: Subjects will receive 2 infusions of rituximab (1000 mg IV), two weeks apart. Methylprednisolone: Subjects will receive methylprednisolone 100 mg IV as premedication to the rituximab infusion. |
| OG001 | Placebo | Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV. All subjects will be treated with an acetaminophen tablet and a diphenhydramine hydrochloride tablet before the infusion. Saline: Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV. |
|
|
|
| Secondary | 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. | Analysis was intent to treat. The last observation was carried forward from the subjects who dropped out before (or at) 24 weeks. | Posted | Number | percentage of participants | 6 months after first infusion, 12 months after first infusion |
|
|
|
|
| Secondary | 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) ). | Intention to treat analysis | Posted | Number | participants | baseline, 6 months after first infusion |
|
|
|
| Secondary | 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. | Posted | Mean | Standard Deviation | mm | baseline, 12 months after first infusion |
|
|
|
|
| Secondary | 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. | Intention to treat analysis | Posted | Median | Inter-Quartile Range | mm | baseline, 6 months after first infusion |
|
|
|
|
| Secondary | 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). | Intention to treat analysis | Posted | Median | Inter-Quartile Range | units on a scale | baseline, 6 months after first infusion, 12 months after first infusion |
|
|
|
|
| Secondary | 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. | Posted | Median | Inter-Quartile Range | units on a scale | baseline, 6 months after first infusion, 12 months after first infusion |
|
|
|
|
| Secondary | 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. | Analysis was intent to treat. The last observation was carried forward from the subjects who dropped out before (or at) 52 weeks. | Posted | Number | percentage of participants | one year |
|
|
|
|
| 2 |
| 13 |
| 6 |
| 13 |
| EG001 | Placebo | Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV. All subjects will be treated with an acetaminophen tablet and a diphenhydramine hydrochloride tablet before the infusion. Saline: Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV. | 0 | 12 | 3 | 12 |
| Rash on face | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Acute Bronchitis | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| Vasculitis legs | Blood and lymphatic system disorders | Systematic Assessment |
|
| Significant eye tearing | Eye disorders | Systematic Assessment |
|
| Tongue pain | Gastrointestinal disorders | Systematic Assessment |
|
| Indigestion | Gastrointestinal disorders | Systematic Assessment |
|
| Arthritis of left hip | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Itching of face and scalp | Skin and subcutaneous tissue disorders | Systematic Assessment |
|
| Arthralgia both knees | Musculoskeletal and connective tissue disorders | Systematic Assessment |
|
| Abdominal Discomfort | Gastrointestinal disorders | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | Systematic Assessment |
|
| Left eye conjunctivitis | Infections and infestations | Systematic Assessment |
|
Not provided
Not provided
| D030342 |
| Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D006042 | Goiter |
| D013959 | Thyroid Diseases |
| D004700 | Endocrine System Diseases |
| D006980 | Hyperthyroidism |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
| D011239 | Prednisolone |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| 0.85 |
| No |
| Superiority or Other |
| Deterioration |
|
| No change |
|
| t-test, 2 sided |
| 0.86 |
| No |
| Superiority or Other |
| t-test, 2 sided |
| 0.49 |
| No |
| Superiority or Other |
| 0.64 |
| No |
| Superiority or Other |
| 6 months QoL physical |
|
| 6 months QoL mental |
|
| 12 months QoL physical |
|
| 12 months QoL mental |
|
| 0.91 |
| No |
| Superiority or Other |
| Comparison of the arms for QoL SF-12 physical score at 12 months. | t-test, 2 sided | 0.29 | No | Superiority or Other |
| Comparison of the arms for QoL SF-12 mental score at 12 months. | t-test, 2 sided | 0.18 | No | Superiority or Other |