Thyroid-associated OphthalmopathyPhase 2/3NCT00595335
Trial of Rituximab for Graves' Ophthalmopathy
A Phase 2/3 study testing Rituximab, Saline and Methylprednisolone in people with Thyroid-associated Ophthalmopathy, run by Rebecca Bahn at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- Thyroid-associated Ophthalmopathy
- What is being tested?
- Rituximab, Saline and Methylprednisolone
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 25 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2008to Sep 2013
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase 2/3 Study of Rituximab for Graves' Ophthalmopathy
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.
Read the 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.
- Conditions
- Thyroid-associated Ophthalmopathy
- Being tested
- Rituximab, Saline, Methylprednisolone
- Keywords
- Thyroid-associated ophthalmopathy, Rituximab, Proptosis
- Medical subject headings
- Graves Ophthalmopathy, Exophthalmos
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
RituximabDrug
Also called Rituxan, MabThera
Subjects will receive 2 infusions of rituximab (1000 mg IV), two weeks apart.
SalineDrug
Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV.
Also called Medrol, Solu-Medrol
Subjects will receive methylprednisolone 100 mg IV as premedication to the rituximab infusion.
| Study group | Role | What they receive |
|---|---|---|
| Rituximab | Experimental | Rituximab 1000 mg IV twice at 2-week intervals, each preceded by Methylprednisolone 100 mg IV as premedication to the rituximab infusion. Receives: Drug: Rituximab; Drug: Methylprednisolone |
| Placebo | Placebo comparator | Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV. Receives: Drug: Saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: baseline, 6 months after the first infusion
Secondary outcomes (7)
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.
Measured: 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) ).
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: one year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted16 Jan 2008 (estimated)
- Study startApr 2008
- Primary completionMar 2013
- Study completionSep 2013
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Thyroid-associated OphthalmopathyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 25 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rebecca Bahn
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Center for Research Resources (NCRR)
- Responsible party
- Sponsor-investigator, Rebecca Bahn, Mayo Clinic
- Investigators
- Rebecca S Bahn, MD, Principal investigator, Mayo Clinic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00595335
- Sponsor's protocol ID
- 06-006130
- Other IDs
- R01DK077814-01, UL1RR024150
- Status last verified
- Dec 2015
- First submitted
- 1 Jan 2008
- Last updated
- 1 Jan 2016
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 25343233
Study at a glance
From the registry record, last updated by the sponsor on 1 Jan 2016. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 2/3 Study of Rituximab for Graves' Ophthalmopathy
- ClinicalTrials.gov ID
- NCT00595335
- Acronym / sponsor ID
- 06-006130
- Conditions
- Thyroid-associated Ophthalmopathy
- Keywords
- Thyroid-associated ophthalmopathy, Rituximab, Proptosis
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 25 participants (actual)
- Lead sponsor
- Rebecca BahnUniversity, hospital or other
- Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Center for Research Resources (NCRR)
- Study start
- Apr 2008
- Primary completion
- Mar 2013 (actual)
- Study completion
- Sep 2013 (actual)
- First posted
- 16 Jan 2008 (estimated)
- Results
- Posted 3 Jun 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Rituximab | Experimental | Drug: Rituximab, Drug: MethylprednisoloneRituximab 1000 mg IV twice at 2-week intervals, each preceded by Methylprednisolone 100 mg IV as premedication to the rituximab infusion. |
| Placebo | Placebo comparator | Drug: SalineSubjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV. |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| RituximabAlso: Rituxan, MabTheraSubjects will receive 2 infusions of rituximab (1000 mg IV), two weeks apart. | Drug | Rituximab |
| SalineSubjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV. | Drug | Placebo |
| MethylprednisoloneAlso: Medrol, Solu-MedrolSubjects will receive methylprednisolone 100 mg IV as premedication to the rituximab infusion. | Drug | Rituximab |
Primary outcome
Change in Clinical Activity Score (CAS)
Time frame: 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.
7 secondary outcomes
Failure Rate
Time frame: 6 months after first infusion, 12 months after first infusion
Change in Disease Severity
Time frame: baseline, 6 months after first infusion
Change in Proptosis
Time frame: baseline, 12 months after first infusion
Change in Lid Fissure
Time frame: baseline, 6 months after first infusion
Change in Extraocular Motility
Time frame: 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
Time frame: baseline, 6 months after first infusion, 12 months after first infusion
Failure Rate at One Year
Time frame: one year
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Jan 2016.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 25343233Stan 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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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Rebecca S Bahn, MD principal investigator
Mayo Clinic
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Rituximab, Saline and Methylprednisolone in people with Thyroid-associated Ophthalmopathy, run by Rebecca Bahn at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 1 Jan 2016. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 3 Jun 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Clinical Activity Score (CAS) (time frame: baseline, 6 months after the first infusion). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00595335, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jan 2016.