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Trial record 18 of 8752 for:    Eye AND Eye Diseases

B-cell Depletion Therapy With Rituximab for Thyroid Eye Disease (BetTeRTED)

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ClinicalTrials.gov Identifier: NCT02316691
Recruitment Status : Recruiting
First Posted : December 15, 2014
Last Update Posted : June 11, 2019
Sponsor:
Information provided by (Responsible Party):
Niveditha Mohan, MD, University of Pittsburgh

Brief Summary:
Thyroid eye disease (TED) is an autoimmune inflammation of the orbital tissues that develops in up to 50% of patients with Graves' disease. Although about 80% respond to IVGC initially, the relapse rate is high and about 75% require further surgery despite initial response. Although the natural history of TED is associated with spontaneous remissions after about 1 to 3 years, many irreversible serious ophthalmic and orbital complications can arise during this time. Therefore, there is a need for improved intervention strategies in the early active inflammatory phase of TED, to avoid progression to the cicatricial stage where disease manifestations can only be addressed in a rehabilitative fashion. The primary immunopathogenesis of Graves' disease is considered to be activation of B cells that then produce autoantibody against thyrotropin receptors in the thyroid (TRAb). Like in many autoimmune diseases, the inflammatory CD4+ T cell subset known as Th17 cells is also increased in blood of patients with active Graves' disease; the putative Th17 cytokine, IL-17, is also increased in serum and tears of TED patients. There is also an emerging pathogenic role for Th17 cells that co-express the chemokine receptor CXCR5 and drive autoantibody production. The contribution of Th17 cells to TED is not well defined. This study is an observational, longitudinal, prospective study of patients receiving treatment for thyroid eye disease.

Condition or disease
Thyroid Eye Disease

Detailed Description:

All enrolled subjects will receive Intravenous Glucocorticoid (IVGC) therapy, which is currently the standard of care for TED patients. Subjects will receive the IVGC therapy at a facility chosen by them and their physician. If their disease does not respond to IVGC therapy, they will receive rituximab and/or surgical decompression and/or radiation which is also currently standard of care at a facility chosen by them and their physician. Prior to initiation of treatment and during the course of treatment, study patients will get research labs done along with routine labs and fill out questionnaires regarding their disease symptoms.

We will obtain 30 mL or 2 tablespoons of blood from subjects at initial evaluation and approximately Wk4, Wk 12, Wk 26, Wk 38, and Wk 52 (this may vary depending on when the patient comes in for their follow up visits, but the schedule approximates what is typical for standard of care in these patients) for mechanistic studies.


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Study Type : Observational
Estimated Enrollment : 28 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: B-cell Depletion Therapy With Rituximab for Thyroid Eye Disease
Study Start Date : January 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019

Resource links provided by the National Library of Medicine


Group/Cohort
Thyroid Eye Disease
Blood samples will be drawn from subjects diagnosed with Thyroid Eye Disease. This study is observational. No interventions will be given as part of this study.



Primary Outcome Measures :
  1. Remission of disease activity (decrease in CAS of ≥ 2) at 26 weeks after first rituximab/placebo infusion [ Time Frame: 26 weeks ]
    Remission of symptoms and disease activity by 26 weeks after the first dose of medication. Subjects will be followed for one year to assess relapse


Secondary Outcome Measures :
  1. Remission of disease activity (decrease in CAS of ≥ 2) at 6 and 14 weeks after first rituximab/placebo infusion. [ Time Frame: 6 weeks ]
    Remission of symptoms by week 6 after treatment and again at week 14.

  2. Maintenance of CAS (defined as no worsening of CAS or requirement of other interventions such as surgical decompression/orbital radiation by 26 weeks after first rituximab/placebo infusion . [ Time Frame: 26 weeks ]
    Maintaining an absence of symptoms and disease activity.

  3. Improvement in disease activity, as measured by CAS as a continuous variable at 6, 14, 26, 38 and 52 weeks after first infusion of rituximab, [ Time Frame: 1 year ]
    Improvement in symptoms and disease activity

  4. ll adverse effects related to RTX [ Time Frame: 1 year ]
    Tracking any adverse events or serious adverse events related to rituximab.


Other Outcome Measures:
  1. Efficacy outcome as measured by Time to ≥ 2 points improvement on the CAS. [ Time Frame: 1 year ]
    Time to ≥ 2 points improvement on the CAS.

  2. Efficacy outcome as measured by Decrease in exophthalmos (measured in mm using the same Hertel exophthalmometer and same intercanthal distance for an individual patient). [ Time Frame: 1 year ]
    Decrease in exophthalmos (measured in mm using the same Hertel exophthalmometer and same intercanthal distance for an individual patient).

  3. Efficacy outcome [ Time Frame: 1 year ]
    Decrease in lid aperture (distance between the lid margins in mm with patient looking in the primary position, sitting relaxed and with distant fixation).

  4. Efficacy outcome as measured by Subjective diplopia score [ Time Frame: 1 year ]
    Subjective diplopia score (0=no diplopia; 1=intermittent, i.e. diplopia in primary position of gaze, when tired or when first awakening; 2= inconstant, i.e. diplopia at extremes of gaze; 3=constant, i.e. continuous diplopia in primary or reading position).

  5. Efficacy outcome as measured by Improvement in quality of life as measured by an SF-36 and GoQoL. [ Time Frame: 1 year ]
    Improvement in quality of life as measured by an SF-36 and GoQoL.

  6. Efficacy outcome as measured by Immunologic markers and mechanistic analyses to include studies of peripheral blood and thyroid B and T cells and autoantibody levels, thyroid volume, cellularity and function. [ Time Frame: 1 year ]
    Immunologic markers and mechanistic analyses to include studies of peripheral blood and thyroid B and T cells and autoantibody levels, thyroid volume, cellularity and function.


Biospecimen Retention:   Samples Without DNA
Samples will be used to determine longitudinal effect of B cell depletion on frequencies and functions of T helper subsets and memory B cells in blood. Any unused PBMC as well as serum obtained from these blood draws will be banked for future use in in vitro experiments.


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
The study will be introduced during a clinic visit with one of the physicians who are investigators on this study. These will be subjects who are being referred for intravenous glucocorticoid (IVGC) therapy due to the severe nature of their thyroid eye disease.
Criteria

Inclusion Criteria:

  1. Willing and able to give informed consent
  2. Age 18 to 75 years of age
  3. Diagnosis of Thyroid Eye Disease (TED) with a CAS of ≥ 3. (Thyroid status can be euthyroid, hyper or hypothyroid.)
  4. Willingness to practice birth control for at least 12 months post treatment.
  5. Normal organ function, except if abnormal due to tumor involvement.
  6. Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months after completion of treatment.
  7. Subject has provided written informed consent.
  8. Documentation of CD20 + status (for B cell malignancies).
  9. ANC: > 1000/mm3
  10. Adequate bone marrow function as indicated by a total white blood cell count of > 4 x 109/, hemoglobin of > 7 g/dl or a platelet count >100,000/mm³
  11. Adequate renal function as indicated by creatinine of <2.5.
  12. Adequate liver function, as indicated by AST or ALT <2x Upper Limit of normal unless related to primary disease.

Exclusion Criteria:

Patients will be excluded from the study based on the following criteria:

  1. Brittle insulin dependent diabetes [The term "brittle" refers to cases of diabetes in which there is an instability that leads to a disruption of life and often recurrent and/ or prolonged hospitalization]
  2. Pregnant or nursing patients
  3. Significant medical comorbidities that would make the risk of high dose steroids intolerable such as severe CHF, CAD, arrhythmias, renal insufficiency, infection or immune deficiency, systemic autoimmune disease, severe glaucoma etc.
  4. Absolute neutrophil count < 1500/mm³.
  5. Contraindication to use of rituximab
  6. Positive PPD and/or Quantiferon Gold TB test without prior anti-tuberculous therapy; active TB
  7. HIV or hepatitis infection or declined consent for HIV or hepatitis testing
  8. Use of rituximab in the prior 24 months for any reason other than TED
  9. Unwillingness to practice birth control for at least 12 months post treatment
  10. Pregnancy (a negative serum pregnancy test should be performed for all women of childbearing potential within 7 days of treatment), or lactating.
  11. Inability to comply with study and/or follow-up procedures.
  12. History of HIV.
  13. Presence of active infection.
  14. Presence of CNS metastases.
  15. New York Heart Association Classification III or IV heart disease (See Appendix D).
  16. Concomitant malignancies or previous malignancies within the last five years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix.
  17. History of psychiatric disorder.
  18. At the Investigator's discretion, receipt of a live vaccine within 4 weeks prior to randomization.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02316691


Contacts
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Contact: Niveditha Mohan, MD 412-647-2632 mohann2@upmc.edu

Locations
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United States, Pennsylvania
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15261
Contact: Niveditha Mohan, MD    412-647-2632    mohann2@upmc.edu   
Principal Investigator: Niveditha Mohan, MD         
Sponsors and Collaborators
University of Pittsburgh
Investigators
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Principal Investigator: Niveditha Mohan, MD University of Pittsburgh Medical Center

Publications of Results:

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Responsible Party: Niveditha Mohan, MD, Assistant Professor of Medicine, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT02316691     History of Changes
Other Study ID Numbers: PRO14060524
UL1TR000005 ( U.S. NIH Grant/Contract )
First Posted: December 15, 2014    Key Record Dates
Last Update Posted: June 11, 2019
Last Verified: June 2019

Keywords provided by Niveditha Mohan, MD, University of Pittsburgh:
Graves Disease
Rituximab

Additional relevant MeSH terms:
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Thyroid Diseases
Eye Diseases
Graves Ophthalmopathy
Endocrine System Diseases
Eye Diseases, Hereditary
Graves Disease
Orbital Diseases
Genetic Diseases, Inborn
Autoimmune Diseases
Immune System Diseases
Exophthalmos
Goiter
Hyperthyroidism
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents