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Trial of Rituximab for Graves' Ophthalmopathy

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ClinicalTrials.gov Identifier: NCT00595335
Recruitment Status : Completed
First Posted : January 16, 2008
Results First Posted : June 3, 2014
Last Update Posted : January 1, 2016
Sponsor:
Collaborators:
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Center for Research Resources (NCRR)
Information provided by (Responsible Party):
Rebecca Bahn, Mayo Clinic

Tracking Information
First Submitted Date  ICMJE January 1, 2008
First Posted Date  ICMJE January 16, 2008
Results First Submitted Date  ICMJE March 26, 2014
Results First Posted Date  ICMJE June 3, 2014
Last Update Posted Date January 1, 2016
Study Start Date  ICMJE April 2008
Actual Primary Completion Date March 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 5, 2014)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: January 15, 2008)
Improvement in Clinical Activity Score by 2 or more points [ Time Frame: 2,4,6 and 12 months after the first infusion ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2014)
  • Failure Rate [ Time Frame: 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.
  • Change in Disease Severity [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.
  • Change in Extraocular Motility [ Time Frame: 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).
  • 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 ]
    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 [ Time Frame: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 15, 2008)
  • Decrease in disease severity by ≥2 NOSPECS classes [ Time Frame: 2,4,6 and 12 months after first infusion ]
  • Decrease in proptosis by ≥2 mm [ Time Frame: 2,4,6 and 12 months after first infusion ]
  • Decrease in lid aperture width by ≥3 mm [ Time Frame: 2,4,6 and 12 months after first infusion ]
  • Improvement in extraocular motility by ≥8 degrees [ Time Frame: 2,4,6 and 12 months after first infusion ]
  • Improvement in a GO-specific quality of life score of ≥ 6 points [ Time Frame: 2,4,6 and 12 months after first infusion ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Trial of Rituximab for Graves' Ophthalmopathy
Official Title  ICMJE Phase 2/3 Study of Rituximab for Graves' Ophthalmopathy
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Thyroid-associated Ophthalmopathy
Intervention  ICMJE
  • Drug: Rituximab
    Subjects will receive 2 infusions of rituximab (1000 mg IV), two weeks apart.
    Other Names:
    • Rituxan
    • MabThera
  • Drug: Saline
    Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV.
  • Drug: Methylprednisolone
    Subjects will receive methylprednisolone 100 mg IV as premedication to the rituximab infusion.
    Other Names:
    • Medrol
    • Solu-Medrol
Study Arms  ICMJE
  • Experimental: Rituximab
    Rituximab 1000 mg IV twice at 2-week intervals, each preceded by Methylprednisolone 100 mg IV as premedication to the rituximab infusion.
    Interventions:
    • Drug: Rituximab
    • Drug: Methylprednisolone
  • Placebo Comparator: Placebo
    Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV.
    Intervention: Drug: Saline
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 26, 2013)
25
Original Estimated Enrollment  ICMJE
 (submitted: January 15, 2008)
30
Actual Study Completion Date  ICMJE September 2013
Actual Primary Completion Date March 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00595335
Other Study ID Numbers  ICMJE 06-006130
R01DK077814-01 ( U.S. NIH Grant/Contract )
UL1RR024150 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Rebecca Bahn, Mayo Clinic
Study Sponsor  ICMJE Rebecca Bahn
Collaborators  ICMJE
  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
  • National Center for Research Resources (NCRR)
Investigators  ICMJE
Principal Investigator: Rebecca S Bahn, MD Mayo Clinic
PRS Account Mayo Clinic
Verification Date December 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP