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Rituximab Treatment of Graves' Dysthyroid Ophthalmopathy

Primary Purpose

Graves' Dysthyroid Ophthalmopathy, Thyroid Related Orbitopathy

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Rituximab
Sponsored by
Silkiss, Rona Z., M.D., FACS
About
Eligibility
Locations
Outcomes
Full info

About this trial

This is an interventional treatment trial for Graves' Dysthyroid Ophthalmopathy focused on measuring Graves' Disease, Dysthyroid Ophthalmopathy, Thyroid related orbitopathy

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Patients eighteen years of age or older.Diagnosed with Graves' dysthyroid ophthalmopathy within one year of presentation.
  • Manifest significant ophthalmic findings of active Graves' disease. (Clinical activity score 4 or greater)
  • Evidence of thyroid abnormality (hyper or hypo thyroid) prior to thyroid treatment
  • Elevated thyroid stimulating immunoglobulin, antithyroid peroxidase antibody or antithyroglobulin antibody.

Exclusion Criteria:

Long standing chronic disease. (greater than one year) History of ineffective prior orbital irradiation. Clinical activity score of less than 4.

  • ANC < 1.5 x 103
  • Hemoglobin: < 8.5 gm/dL
  • Platelets: < 100,000/mm
  • AST or ALT >2.5 x Upper Limit of Normal unless related to primary disease.
  • IgG: < 5.6 mg/dl and IgM: < .55 mg/dl
  • Positive Hepatitis B or C serology (Hep B Surface antigen and Hep C antibody)
  • History of positive HIV (HIV conducted during screening if applicable)
  • Treatment with any investigational agent within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer)
  • Receipt of a live vaccine within 4 weeks prior to randomization
  • Previous Treatment with Rituximab (MabThera® / Rituxan®)
  • History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies
  • History of recurrent significant infection or history of recurrent bacterial infections
  • Known active bacterial, viral fungal mycobacterial, or other infection (including tuberculosis or atypical, mycobacterial disease, but excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with i.v. antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening
  • Lack of peripheral venous access
  • History of drug, alcohol, or chemical abuse within 6 months prior to screening
  • Pregnancy (a negative serum pregnancy test should be performed for all women of childbearing potential within 7 days of treatment) or lactation
  • Concomitant malignancies or previous malignancies, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix
  • History of psychiatric disorder that would interfere with normal participation in this protocol
  • Significant cardiac, including significant or uncontrolled arrhythmia, or pulmonary disease (including obstructive pulmonary disease)
  • History of systemic lupus erythematosis
  • Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications.

Inability to comply with study and follow-up procedures

-

Sites / Locations

  • Rona Z. Silkiss, MD, FACS
  • Simeon A. Lauer, MD

Outcomes

Primary Outcome Measures

Clinical response to treatment, alteration in immunoglobulin levels
To assess the safety and tolerability of Rituximab in Graves' dysthyroid disease up to 24 weeks. Adverse and serious adverse events during the study period, reasonably or probably related to Rituximab, will be assessed at each study visit up to 12 month
Efficacy:
A significant (25%) reduction in progression of Thyroid Associated Ophthalmopathy or disease activity as measured by the thyroid associated ophthalmopathy scale (University of British Columbia Thyroid Orbitopathy Inflammatory Score) up to 24 weeks.

Secondary Outcome Measures

To evaluate for a reduction in disease activity as measured by:
Reduction (25%) of elevated antibody levels- serum thyroid stimulating immunoglobulin (TSI), antithyroidperoxidase antibody (TPO) or antithyroglobulin levels at 24 weeks.
MRI of the orbit with coronal and axial views to evaluate evidence of optic nerve crowding, muscle size reduction or decreased proptosis during treatment and follow up interval at 24 weeks.

Full Information

First Posted
January 17, 2007
Last Updated
October 4, 2010
Sponsor
Silkiss, Rona Z., M.D., FACS
Collaborators
Lauer, Simeon, M.D., Reier, Alice M.D., Coleman, Morton M.D.
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1. Study Identification

Unique Protocol Identification Number
NCT00424151
Brief Title
Rituximab Treatment of Graves' Dysthyroid Ophthalmopathy
Official Title
Rituximab Treatment of Graves' Dysthyroid Ophthalmopathy Phase I/II
Study Type
Interventional

2. Study Status

Record Verification Date
October 2010
Overall Recruitment Status
Completed
Study Start Date
December 2006 (undefined)
Primary Completion Date
March 2009 (Actual)
Study Completion Date
March 2009 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor
Silkiss, Rona Z., M.D., FACS
Collaborators
Lauer, Simeon, M.D., Reier, Alice M.D., Coleman, Morton M.D.

4. Oversight

5. Study Description

Brief Summary
This study is designed to treat patients with Graves' disease with Rituximab in an attempt to prevent or reverse the physically deforming and debilitating consequences of this disease.
Detailed Description
Graves' Dysthyroid ophthalmopathy is an autoimmune disease characterized by inflammatory changes of the periocular and orbital region often in association with an underlying thyroid abnormality. These changes can be extremely debilitating and may lead to visual loss. Attempts at limiting or reversing the phenotypic expression of Graves' ophthalmopathy through aggressive orbital decompression surgery or targeting the inflammatory disease, using high dose systemic corticosteroids and/or orbital radiotherapy, have been limited to date by treatment ineffectiveness and co-morbidities. Selective B-cell depletion therapy offers a potential treatment alternative. This study is designed to treat patients with Graves' disease with Rituximab in an attempt to prevent or reverse the physically deforming and debilitating consequences of this disease.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Graves' Dysthyroid Ophthalmopathy, Thyroid Related Orbitopathy
Keywords
Graves' Disease, Dysthyroid Ophthalmopathy, Thyroid related orbitopathy

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
12 (Actual)

8. Arms, Groups, and Interventions

Intervention Type
Drug
Intervention Name(s)
Rituximab
Primary Outcome Measure Information:
Title
Clinical response to treatment, alteration in immunoglobulin levels
Time Frame
One year post infusion
Title
To assess the safety and tolerability of Rituximab in Graves' dysthyroid disease up to 24 weeks. Adverse and serious adverse events during the study period, reasonably or probably related to Rituximab, will be assessed at each study visit up to 12 month
Time Frame
One year
Title
Efficacy:
Time Frame
One year after treatment
Title
A significant (25%) reduction in progression of Thyroid Associated Ophthalmopathy or disease activity as measured by the thyroid associated ophthalmopathy scale (University of British Columbia Thyroid Orbitopathy Inflammatory Score) up to 24 weeks.
Time Frame
One year
Secondary Outcome Measure Information:
Title
To evaluate for a reduction in disease activity as measured by:
Time Frame
One year
Title
Reduction (25%) of elevated antibody levels- serum thyroid stimulating immunoglobulin (TSI), antithyroidperoxidase antibody (TPO) or antithyroglobulin levels at 24 weeks.
Time Frame
One year
Title
MRI of the orbit with coronal and axial views to evaluate evidence of optic nerve crowding, muscle size reduction or decreased proptosis during treatment and follow up interval at 24 weeks.
Time Frame
Six months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Patients eighteen years of age or older.Diagnosed with Graves' dysthyroid ophthalmopathy within one year of presentation. Manifest significant ophthalmic findings of active Graves' disease. (Clinical activity score 4 or greater) Evidence of thyroid abnormality (hyper or hypo thyroid) prior to thyroid treatment Elevated thyroid stimulating immunoglobulin, antithyroid peroxidase antibody or antithyroglobulin antibody. Exclusion Criteria: Long standing chronic disease. (greater than one year) History of ineffective prior orbital irradiation. Clinical activity score of less than 4. ANC < 1.5 x 103 Hemoglobin: < 8.5 gm/dL Platelets: < 100,000/mm AST or ALT >2.5 x Upper Limit of Normal unless related to primary disease. IgG: < 5.6 mg/dl and IgM: < .55 mg/dl Positive Hepatitis B or C serology (Hep B Surface antigen and Hep C antibody) History of positive HIV (HIV conducted during screening if applicable) Treatment with any investigational agent within 4 weeks of screening or 5 half-lives of the investigational drug (whichever is longer) Receipt of a live vaccine within 4 weeks prior to randomization Previous Treatment with Rituximab (MabThera® / Rituxan®) History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies History of recurrent significant infection or history of recurrent bacterial infections Known active bacterial, viral fungal mycobacterial, or other infection (including tuberculosis or atypical, mycobacterial disease, but excluding fungal infections of nail beds) or any major episode of infection requiring hospitalization or treatment with i.v. antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening Lack of peripheral venous access History of drug, alcohol, or chemical abuse within 6 months prior to screening Pregnancy (a negative serum pregnancy test should be performed for all women of childbearing potential within 7 days of treatment) or lactation Concomitant malignancies or previous malignancies, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix History of psychiatric disorder that would interfere with normal participation in this protocol Significant cardiac, including significant or uncontrolled arrhythmia, or pulmonary disease (including obstructive pulmonary disease) History of systemic lupus erythematosis Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications. Inability to comply with study and follow-up procedures -
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rona Z Silkiss, MD
Organizational Affiliation
California Pacific Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Rona Z. Silkiss, MD, FACS
City
Oakland
State/Province
California
ZIP/Postal Code
94609
Country
United States
Facility Name
Simeon A. Lauer, MD
City
New York
State/Province
New York
ZIP/Postal Code
10021
Country
United States

12. IPD Sharing Statement

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Rituximab Treatment of Graves' Dysthyroid Ophthalmopathy

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