Trial of Rituximab for Graves' Ophthalmopathy
Condition: Thyroid-associated Ophthalmopathy
MeSH terms: Eye Diseases; Graves Ophthalmopathy
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Intervention name(s): Rituximab; Saline; Methylprednisolone
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Subjects will receive 2 infusions of rituximab (1000 mg IV), two weeks apart.; Subjects will receive 2 infusions of saline IV, 2 weeks apart, each preceded by a premedication saline IV.; Subjects will receive methylprednisolone 100 mg IV as premedication to the rituximab infusion.
Other intervention name(s): Rituxan; MabThera; Medrol; Solu-Medrol
Intervention MeSH terms: Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Rituximab; Prednisolone hemisuccinate; Prednisolone phosphate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Thyroid-associated ophthalmopathy; Rituximab; Proptosis