Thyroid-associated Ophthalmopathy
Conditions
Keywords
Thyroid-associated ophthalmopathy, Rituximab, Proptosis
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.
Interventions
DRUGRituximab
Subjects will receive 2 infusions of rituximab (1000 mg IV), two weeks apart.
DRUGSaline
Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV.
DRUGMethylprednisolone
Subjects will receive methylprednisolone 100 mg IV as premedication to the rituximab infusion.
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Center for Research Resources (NCRR)
Rebecca Bahn
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Clinical Activity Score (CAS) | baseline, 6 months after the first infusion | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Disease Severity | baseline, 6 months after first 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) ). |
| Change in Proptosis | baseline, 12 months after first infusion | 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. |
| Change in Lid Fissure | baseline, 6 months after first infusion | 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. |
| Failure Rate | 6 months after first infusion, 12 months after first infusion | 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. |
| Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | baseline, 6 months after first infusion, 12 months after first infusion | 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. |
| Failure Rate at One Year | 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. |
| Change in Extraocular Motility | baseline, 6 months after first infusion, 12 months after first infusion | 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). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 13 |
| 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. | 12 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Baseline to Six Months | Adverse Event | 1 | 0 |
| Baseline to Six Months | Disease Progression | 1 | 1 |
| Baseline to Six Months | Withdrawal by Subject | 0 | 1 |
| Six Months to Twelve Months | Disease Progression | 1 | 0 |
| Six Months to Twelve Months | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Rituximab | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 57.6 years STANDARD_DEVIATION 12.7 | 61.8 years STANDARD_DEVIATION 11 | 58.6 years STANDARD_DEVIATION 11.8 |
| Clinical Activity Score | 4.9 units on a scale STANDARD_DEVIATION 1 | 5.3 units on a scale STANDARD_DEVIATION 1 | 5.1 units on a scale STANDARD_DEVIATION 1 |
| Region of Enrollment United States | 13 participants | 12 participants | 25 participants |
| Sex: Female, Male Female | 9 Participants | 8 Participants | 17 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 13 | 3 / 12 |
| serious Total, serious adverse events | 2 / 13 | 0 / 12 |
Outcome results
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.
Time frame: baseline, 6 months after the first infusion
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rituximab | Change in Clinical Activity Score (CAS) | -1.2 units on a scale | Standard Deviation 2 |
| Placebo | Change in Clinical Activity Score (CAS) | -1.5 units on a scale | Standard Deviation 1.8 |
Comparison: Comparison of the change between the two groups' CAS score at 6 months.p-value: 0.73t-test, 2 sided
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) ).
Time frame: baseline, 6 months after first infusion
Population: Intention to treat analysis
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab | Change in Disease Severity | Improvement by 1 class | 6 participants |
| Rituximab | Change in Disease Severity | Improvement by 2 classes | 2 participants |
| Rituximab | Change in Disease Severity | Deterioration | 2 participants |
| Rituximab | Change in Disease Severity | No change | 3 participants |
| Placebo | Change in Disease Severity | No change | 2 participants |
| Placebo | Change in Disease Severity | Improvement by 1 class | 8 participants |
| Placebo | Change in Disease Severity | Deterioration | 0 participants |
| Placebo | Change in Disease Severity | Improvement by 2 classes | 2 participants |
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).
Time frame: baseline, 6 months after first infusion, 12 months after first infusion
Population: Intention to treat analysis
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rituximab | Change in Extraocular Motility | Change baseline-6 months | 3 units on a scale |
| Rituximab | Change in Extraocular Motility | Change baseline-12 months | 2 units on a scale |
| Placebo | Change in Extraocular Motility | Change baseline-6 months | 2.5 units on a scale |
| Placebo | Change in Extraocular Motility | Change baseline-12 months | 1.5 units on a scale |
Comparison: Comparison of change between groups in extraocular motility at 6 months.p-value: 0.21t-test, 2 sided
Comparison: Comparison of change between groups in extraocular motility at 12 months.p-value: 0.64t-test, 2 sided
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.
Time frame: baseline, 6 months after first infusion
Population: Intention to treat analysis
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rituximab | Change in Lid Fissure | Lid fissure right eye | 0 mm |
| Rituximab | Change in Lid Fissure | Lid fissure left eye | 0 mm |
| Placebo | Change in Lid Fissure | Lid fissure right eye | 0 mm |
| Placebo | Change in Lid Fissure | Lid fissure left eye | 0.5 mm |
Comparison: Comparison of the change in lid fissure in the right eye between the two groups.p-value: 0.98t-test, 2 sided
Comparison: Comparison of the change in lid fissure in the left eye between the two groups.p-value: 0.49t-test, 2 sided
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.
Time frame: baseline, 12 months after first infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Rituximab | Change in Proptosis | Proptosis right eye | 0.82 mm | Standard Deviation 1.4 |
| Rituximab | Change in Proptosis | Proptosis left eye | 0.1 mm | Standard Deviation 1.2 |
| Placebo | Change in Proptosis | Proptosis right eye | 0.80 mm | Standard Deviation 1.3 |
| Placebo | Change in Proptosis | Proptosis left eye | 0.0 mm | Standard Deviation 1.8 |
Comparison: Comparison of the change between the two groups in proptosis in the right eye at 12 months.p-value: 0.97t-test, 2 sided
Comparison: Comparison of the change between the two groups in change in proptosis in left eye at 12 months.p-value: 0.86t-test, 2 sided
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.
Time frame: 6 months after first infusion, 12 months after first infusion
Population: Analysis was intent to treat. The last observation was carried forward from the subjects who dropped out before (or at) 24 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Rituximab | Failure Rate | Failure rate at 6 months | 69 percentage of participants |
| Rituximab | Failure Rate | Failure rate at 12 months | 46 percentage of participants |
| Placebo | Failure Rate | Failure rate at 12 months | 50 percentage of participants |
| Placebo | Failure Rate | Failure rate at 6 months | 75 percentage of participants |
Comparison: Comparison of the change between the two groups' failure rate at 6 months.p-value: 0.75Fisher Exact
Comparison: Comparison of the change between the two groups' failure rate at 12 months.p-value: 0.85Fisher Exact
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.
Time frame: one year
Population: Analysis was intent to treat. The last observation was carried forward from the subjects who dropped out before (or at) 52 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | Failure Rate at One Year | 46 percentage of participants |
| Placebo | Failure Rate at One Year | 50 percentage of participants |
Comparison: Comparison of the change between the two groups' failure rate at 12 months.p-value: 0.85Fisher Exact
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.
Time frame: baseline, 6 months after first infusion, 12 months after first infusion
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Rituximab | Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | Baseline QoL physical | 53.2 units on a scale |
| Rituximab | Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | Baseline QoL mental | 44.3 units on a scale |
| Rituximab | Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | 6 months QoL physical | 45.9 units on a scale |
| Rituximab | Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | 6 months QoL mental | 52.8 units on a scale |
| Rituximab | Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | 12 months QoL physical | 51.8 units on a scale |
| Rituximab | Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | 12 months QoL mental | 56.1 units on a scale |
| Placebo | Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | 12 months QoL physical | 46.7 units on a scale |
| Placebo | Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | Baseline QoL physical | 39.9 units on a scale |
| Placebo | Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | 6 months QoL mental | 46.1 units on a scale |
| Placebo | Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | Baseline QoL mental | 46.1 units on a scale |
| Placebo | Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | 12 months QoL mental | 49.4 units on a scale |
| Placebo | Graves' Ophthalmopathy Quality of Life Score Using the Short Form-12 (SF-12) Health Survey | 6 months QoL physical | 40.3 units on a scale |
Comparison: Comparison of the arms for QoL SF-12 physical score at 6 months.p-value: 0.36t-test, 2 sided
Comparison: Comparison of the arms for QoL SF-12 mental score at 6 months.p-value: 0.91t-test, 2 sided
Comparison: Comparison of the arms for QoL SF-12 physical score at 12 months.p-value: 0.29t-test, 2 sided
Comparison: Comparison of the arms for QoL SF-12 mental score at 12 months.p-value: 0.18t-test, 2 sided