B-cell Depletion Therapy With Rituximab for Thyroid Eye Disease

Thyroid Eye Disease Clinical Trial

— BetTeRTED  

Official title:

B-cell Depletion Therapy With Rituximab for Thyroid Eye Disease

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02316691
• Other study ID #: PRO14060524
• Secondary ID: UL1TR000005
• Status: Terminated
• Start date: January 2016
• Est. completion date: November 2019

Study information

• Verified date: November 2019
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2
• Est. completion date: November 2019
• Est. primary completion date: November 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Eye Diseases
• Graves Ophthalmopathy
• Thyroid Diseases
• Thyroid Eye Disease

Locations

Country	Name	City	State
United States	University of Pittsburgh	Pittsburgh	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
University of Pittsburgh

Country where clinical trial is conducted

United States, 

References & Publications (15)

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

Bartalena L, Baldeschi L, Dickinson A, Eckstein A, Kendall-Taylor P, Marcocci C, Mourits M, Perros P, Boboridis K, Boschi A, Currò N, Daumerie C, Kahaly GJ, Krassas GE, Lane CM, Lazarus JH, Marinò M, Nardi M, Neoh C, Orgiazzi J, Pearce S, Pinchera A, Pitz — View Citation

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. Review. — View Citation

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. Review. — View Citation

HALES IB, RUNDLE FF. Ocular changes in Graves' disease. A long-term follow-up study. Q J Med. 1960 Jan;29:113-26. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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 co — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. Review. — View Citation

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. — View Citation

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

* Note: There are 15 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Efficacy outcome as measured by Time to = 2 points improvement on the CAS.	Time to = 2 points improvement on the CAS.	1 year
Other	Efficacy outcome as measured by Decrease in exophthalmos (measured in mm using the same Hertel exophthalmometer and same intercanthal distance for an individual patient).	Decrease in exophthalmos (measured in mm using the same Hertel exophthalmometer and same intercanthal distance for an individual patient).	1 year
Other	Efficacy outcome	Decrease in lid aperture (distance between the lid margins in mm with patient looking in the primary position, sitting relaxed and with distant fixation).	1 year
Other	Efficacy outcome as measured by Subjective diplopia score	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).	1 year
Other	Efficacy outcome as measured by Improvement in quality of life as measured by an SF-36 and GoQoL.	Improvement in quality of life as measured by an SF-36 and GoQoL.	1 year
Other	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.	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.	1 year
Primary	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	Remission of disease activity (decrease in CAS of = 2) at 6 and 14 weeks after first rituximab/placebo infusion.	Remission of symptoms by week 6 after treatment and again at week 14.	6 weeks
Secondary	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 .	Maintaining an absence of symptoms and disease activity.	26 weeks
Secondary	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,	Improvement in symptoms and disease activity	1 year
Secondary	ll adverse effects related to RTX	Tracking any adverse events or serious adverse events related to rituximab.	1 year