B-cell Depletion Therapy With Rituximab for Thyroid Eye Disease

NCT02316691 | Terminated

• 2 other identifiers: PRO14060524UL1TR000005
• Study Type: observational
• Target: 2
• Locations: 1 country
• Sites: 1

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.

Conditions

Thyroid Eye Disease

Keywords

Graves Disease; Rituximab

Outcome Measures

Primary Outcomes (1)

• Remission of disease activity (decrease in CAS of ≥ 2) at 26 weeks after first rituximab/placebo infusion

  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

  26 weeks

Secondary Outcomes (4)

• Remission of disease activity (decrease in CAS of ≥ 2) at 6 and 14 weeks after first rituximab/placebo infusion.

  6 weeks

• 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 .

  26 weeks

• 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,

  1 year

• ll adverse effects related to RTX

  1 year

Other Outcomes (6)

• Efficacy outcome as measured by Time to ≥ 2 points improvement on the CAS.

  1 year

• Efficacy outcome as measured by Decrease in exophthalmos (measured in mm using the same Hertel exophthalmometer and same intercanthal distance for an individual patient).

  1 year

• Efficacy outcome

  1 year

Study Arms (1)

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.

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• Willing and able to give informed consent
• Age 18 to 75 years of age
• Diagnosis of Thyroid Eye Disease (TED) with a CAS of ≥ 3. (Thyroid status can be euthyroid, hyper or hypothyroid.)
• Willingness to practice birth control for at least 12 months post treatment.
• Normal organ function, except if abnormal due to tumor involvement.
• 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.
• Subject has provided written informed consent.
• Documentation of CD20 + status (for B cell malignancies).
• ANC: \> 1000/mm3
• 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
• Adequate renal function as indicated by creatinine of \<2.5.
• Adequate liver function, as indicated by AST or ALT \<2x Upper Limit of normal unless related to primary disease.

You may not qualify if:

• Patients will be excluded from the study based on the following criteria:
• Brittle insulin dependent diabetes \[The term "brittle" refers to cases of diabetes in which there is an instability that leads to a disruption of life and often recurrent and/ or prolonged hospitalization\]
• Pregnant or nursing patients
• 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.
• Absolute neutrophil count \< 1500/mm³.
• Contraindication to use of rituximab
• Positive PPD and/or Quantiferon Gold TB test without prior anti-tuberculous therapy; active TB
• HIV or hepatitis infection or declined consent for HIV or hepatitis testing
• Use of rituximab in the prior 24 months for any reason other than TED
• Unwillingness to practice birth control for at least 12 months post treatment
• Pregnancy (a negative serum pregnancy test should be performed for all women of childbearing potential within 7 days of treatment), or lactating.
• Inability to comply with study and/or follow-up procedures.
• History of HIV.
• Presence of active infection.
• Presence of CNS metastases.

Sponsors & Collaborators

• University of Pittsburgh: lead

Study Sites (1)

University of Pittsburgh

Pittsburgh, Pennsylvania, 15261, United States

Location

Related Publications (15)

• Bahn RS. Graves' ophthalmopathy. N Engl J Med. 2010 Feb 25;362(8):726-38. doi: 10.1056/NEJMra0905750.

  PMID: 20181974 RESULT

• Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Curro N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marino M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz S, Salvi M, Sivelli P, Stahl M, von Arx G, Wiersinga WM; European Group on Graves' Orbitopathy (EUGOGO). Consensus statement of the European Group on Graves' orbitopathy (EUGOGO) on management of GO. Eur J Endocrinol. 2008 Mar;158(3):273-85. doi: 10.1530/EJE-07-0666. No abstract available.

  PMID: 18299459 RESULT

• Yeatts RP. Quality of life in patients with Graves ophthalmopathy. Trans Am Ophthalmol Soc. 2005;103:368-411.

  PMID: 17057811 RESULT

• HALES IB, RUNDLE FF. Ocular changes in Graves' disease. A long-term follow-up study. Q J Med. 1960 Jan;29:113-26. No abstract available.

  PMID: 14398978 RESULT

• Stan MN, Garrity JA, Bahn RS. The evaluation and treatment of graves ophthalmopathy. Med Clin North Am. 2012 Mar;96(2):311-28. doi: 10.1016/j.mcna.2012.01.014. Epub 2012 Feb 22.

  PMID: 22443978 RESULT

• Wakelkamp IM, Bakker O, Baldeschi L, Wiersinga WM, Prummel MF. TSH-R expression and cytokine profile in orbital tissue of active vs. inactive Graves' ophthalmopathy patients. Clin Endocrinol (Oxf). 2003 Mar;58(3):280-7. doi: 10.1046/j.1365-2265.2003.01708.x.

  PMID: 12608932 RESULT

• Douglas RS, Gupta S. The pathophysiology of thyroid eye disease: implications for immunotherapy. Curr Opin Ophthalmol. 2011 Sep;22(5):385-90. doi: 10.1097/ICU.0b013e3283499446.

  PMID: 21730841 RESULT

• Tuscano JM, Harris GS, Tedder TF. B lymphocytes contribute to autoimmune disease pathogenesis: current trends and clinical implications. Autoimmun Rev. 2003 Mar;2(2):101-8. doi: 10.1016/s1568-9972(02)00148-9.

  PMID: 12848966 RESULT

• Shen S, Chan A, Sfikakis PP, Hsiu Ling AL, Detorakis ET, Boboridis KG, Mavrikakis I. B-cell targeted therapy with rituximab for thyroid eye disease: closer to the clinic. Surv Ophthalmol. 2013 May-Jun;58(3):252-65. doi: 10.1016/j.survophthal.2012.10.006. Epub 2012 Dec 17.

  PMID: 23253433 RESULT

• Gaffen SL. Recent advances in the IL-17 cytokine family. Curr Opin Immunol. 2011 Oct;23(5):613-9. doi: 10.1016/j.coi.2011.07.006. Epub 2011 Aug 16.

  PMID: 21852080 RESULT

• Peng D, Xu B, Wang Y, Guo H, Jiang Y. A high frequency of circulating th22 and th17 cells in patients with new onset graves' disease. PLoS One. 2013 Jul 11;8(7):e68446. doi: 10.1371/journal.pone.0068446. Print 2013.

  PMID: 23874630 RESULT

• Kim SE, Yoon JS, Kim KH, Lee SY. Increased serum interleukin-17 in Graves' ophthalmopathy. Graefes Arch Clin Exp Ophthalmol. 2012 Oct;250(10):1521-6. doi: 10.1007/s00417-012-2092-7. Epub 2012 Jul 1.

  PMID: 22752189 RESULT

• Huang D, Xu N, Song Y, Wang P, Yang H. Inflammatory cytokine profiles in the tears of thyroid-associated ophthalmopathy. Graefes Arch Clin Exp Ophthalmol. 2012 Apr;250(4):619-25. doi: 10.1007/s00417-011-1863-x. Epub 2011 Nov 30.

  PMID: 22124787 RESULT

• Ma CS, Deenick EK. Human T follicular helper (Tfh) cells and disease. Immunol Cell Biol. 2014 Jan;92(1):64-71. doi: 10.1038/icb.2013.55. Epub 2013 Oct 22.

  PMID: 24145858 RESULT

• Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, Foucat E, Dullaers M, Oh S, Sabzghabaei N, Lavecchio EM, Punaro M, Pascual V, Banchereau J, Ueno H. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011 Jan 28;34(1):108-21. doi: 10.1016/j.immuni.2010.12.012. Epub 2011 Jan 6.

  PMID: 21215658 RESULT

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.

MeSH Terms

Conditions

Graves Ophthalmopathy; Graves Disease

Condition Hierarchy (Ancestors)

Eye Diseases, Hereditary; Eye Diseases; Exophthalmos; Orbital Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Goiter; Thyroid Diseases; Endocrine System Diseases; Hyperthyroidism; Autoimmune Diseases; Immune System Diseases

Study Officials

• Niveditha Mohan, MD

  University of Pittsburgh Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: December 8, 2014
• First Posted: December 15, 2014
• Study Start: January 1, 2016
• Primary Completion: November 1, 2019
• Study Completion: November 1, 2019
• Last Updated: November 18, 2019

Record last verified: 2019-11

Locations

US (1)