Clinical trial NCT06367517: Tocilizumab in Corticosteroid-Resistant Graves' Orbitopathy (Thyroid Eye Disease)
Official title: Efficacy and Safety of Tocilizumab in Patients With Active Moderate-to-Severe Corticosteroid-Resistant Thyroid Eye Disease: Open, Prospective, Observational Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Orbitopathy, Graves
Thyroid Eye Disease
Ophthalmopathy
Keywords: Graves' disease
Graves' orbitopathy
Tocilizumab
Thyroid Eye Disease
Hyperthyroidism
Lead sponsor: Medical University of Warsaw
Sponsor class: OTHER
First posted: 2024-04-16
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Consecutive patients with active, moderate-to-severe Graves' orbitopathy (GO), resistant to corticosteroid treatment, will be enrolled to participate in the study. They will be diagnosed and treated at a tertiarry referall center.

Brief summary: The aim of this study is to evaluate the efficacy and safety of Tocilizumab as second/third line treatment in patients with Active Moderate-to-Severe Corticosteroid-Resistant Thyroid Eye Disease.

Detailed description: Graves' Orbitopathy (GO) is an autoimmune disease that involves orbital tissues, leading to temporary or permanent damage to the eye. Although GO is a rare condition, it negatively affects the quality of life in the majority of patients. In the majority of european centers, high-dose intravenous glucocorticoid (GCs) therapy remains the first-line treatment in patients with active, moderate-to-severe GO. However, GCs are effective in only 45-60% of patients, with a high probability of diseases relapse (10-40%) or disease progression to dysthyroid optic neuropathy (up to 10%). Due to limited efficacy of GCs, unpredictable relapses and progression of GO, the management of GO remains a challenge.

A few studies have demonstrated that interleukin-6 (IL-6) blockade with tocilizumab (TCZ) is effective in GC-refractory GO. However, the long-term outcomes of TCZ remain scarce.

Therefore, the investigators are planning to assess the therapy with Tocilizumab, regarding clinical outcomes and adverse events. The investigators plan to include a total of 30 patients with active, moderate-to-severe, corticosteroid-resistant GO over a period of approximately 4 years.

Eligibility criteria: Inclusion Criteria:

* Written informed consent
* Male or female, 18-80 years old
* Patients with active (Clinical Activity Score ≥ 3 in 7-item scale) and moderate-to-severe GO, diagnosed according to the EUGOGO guidelines, after the completion of MP pulse treatment, WITH

  o Deterioration of GO (in 1 or 2 eyes) when two of the following occurred:
* increase in palpebral aperture by at least 2 mm;
* deterioration in CAS by at least 2 points (7-point CAS)
* increase in exophthalmos by at least 2 mm;
* worsening of diplopia (appearance or change in the degree)
* worsening in ocular motility by 8o

  o Incomplete response in both eyes to intravenous methylprednisolone pulse therapy; defined changes smaller than previously defined in any of the mentioned parameters.
* Euthyroid for at least 6-8 weeks (serum free hormone concentrations within 30% of normal range) on either anti-thyroid medications (tyonamides) to control hyperthyroidism or L-thyroxine for replacement therapy for hypothyroidism.
* Negative pregnancy test in women of fertile age.
* All female patients of fertile age must use a reliable contraceptive method to prevent pregnancy during the study period, and at least during a period of six months following the last dose of the investigational medicinal product.

Exclusion Criteria:

* Signs of sight-threatening TED (severe keratopathy, optic neuropathy)
* Pregnant or breastfeeding woman or woman planning to become pregnant during the study
* Patients who could need treatment with radioactive iodine or thyroidectomy during the study
* Treatment with any biological therapy at any time.
* Active infection.
* History of recurrent clinically significant infection or recurrent bacterial infections.
* Positive quantiferon without documentation of treatment for tuberculosis (TB) infection or documentation of no need for such therapy.
* Required management of infections, as follows: currently on any suppressive therapy for a chronic infection, hospitalization for treatment of infection within 60 days before Day 0, use of parenteral antibiotics within 60 days before Day 0, use of oral antibiotics within 30 days before Day 0.
* History of intestinal ulceration or diverticulitis
* Patients with a history of chronic liver disease or liver disorders: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) above 5 times upper limit of normal (ULN)
* HBsAg positive test.
* HBcAb positive test, regardless of HBsAb status, will undergo HBV DNA which, if positive, will be excluded. HbcAb positive, HbsAg negative patients with undetectable HBV DNA will receive antiviral prophylaxis throughout the immunosuppressive therapy.
* Hepatitis C antibody positive test at screening.
* Positive test for Human Immunodeficiency Virus (HIV) antibody at screening or historically. Denied consent to HIV testing.
* Absolute neutrophil count (ANC) \< 2.0 × 109/L or a platelet count \< 100×103/μL
* Alkaline phosphatase and bilirubin\>1.5xULN (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is\<35%).
* Cardiovascular or cerebrovascular disease clinically significant.
* Other serious chronic illness (including uncontrolled diabetes mellitus, renal disease, pulmonary disease, major depression).
* History of sarcoidosis.
* Primary or secondary immunodeficiency.
* History of IgE-mediated or non-IgE-mediated hypersensitivity.
* History of reactions or anaphylactic allergic severe human monoclonal antibodies, humanized or murine.
* Administration of live vaccines given within 30 days prior to administration of (Day 0) or concurrently with tocilizumab (during study).
* Splenectomy.
* Current drug or alcohol abuse or dependence.

Primary outcomes:
measure: Disease improvement
timeFrame: at 16, 24 and 48 weeks
measure: Improvement of quality of life
timeFrame: at 16, 24 and 48 weeks
Secondary outcomes:
measure: Disease inactivation
timeFrame: at 16, 24 and 48 weeks
measure: Proportion of patients achieving response in specific GO signs and symptoms
timeFrame: at 16, 24 and 48 weeks
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
timeFrame: from 0 to 16 weeks
measure: Decrease in concentration of thyrotropin receptor antibodies
timeFrame: at 4, 8, 12, 16, 24 and 48 weeks
measure: Decrease in levels of proinflammatory cytokines
timeFrame: at 4, 8, 12, 16, 24 and 48 weeks
measure: Number of the rehabilitative surgeries performed after immunosuppressive therapy
timeFrame: at 48 weeks
measure: The rate of disease relapse
timeFrame: at 48 weeks
measure: Decrease in proptosis by at least 2 mm assessed using magnetic resonance imaging (MRI)
timeFrame: at 16 weeks
Other outcomes:
Locations:
city: Warsaw
country: Poland
facility: Department of Internal Medicine and Endocrinology, Medical University of Warsaw
Study officials:
affiliation: Medical University of Warsaw
name: Tomasz Bednarczuk, MD, PHD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Burch HB, Perros P, Bednarczuk T, Cooper DS, Dolman PJ, Leung AM, Mombaerts I, Salvi M, Stan MN. Management of Thyroid Eye Disease: A Consensus Statement by the American Thyroid Association and the European Thyroid Association. Thyroid. 2022 Dec;32(12):1439-1470. doi: 10.1089/thy.2022.0251. Epub 2022 Dec 8.
citation: Perez-Moreiras JV, Gomez-Reino JJ, Maneiro JR, Perez-Pampin E, Romo Lopez A, Rodriguez Alvarez FM, Castillo Laguarta JM, Del Estad Cabello A, Gessa Sorroche M, Espana Gregori E, Sales-Sanz M; Tocilizumab in Graves Orbitopathy Study Group. Efficacy of Tocilizumab in Patients With Moderate-to-Severe Corticosteroid-Resistant Graves Orbitopathy: A Randomized Clinical Trial. Am J Ophthalmol. 2018 Nov;195:181-190. doi: 10.1016/j.ajo.2018.07.038. Epub 2018 Aug 4.
citation: Rymuza J, Kus A, Bialas-Niedziela D, Turczynska M, Kecik D, Bednarczuk T. Long-term remission of corticosteroid-resistant Graves' orbitopathy after therapy with tocilizumab. Endokrynol Pol. 2024;75(1):117-118. doi: 10.5603/ep.97224.
citation: Bartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, Marino M, Vaidya B, Wiersinga WM; EUGOGO dagger. The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy. Eur J Endocrinol. 2021 Aug 27;185(4):G43-G67. doi: 10.1530/EJE-21-0479.
citation: Sawicka-Gutaj N, Bednarczuk T, Daroszewski J, Waligorska-Stachura J, Miskiewicz P, Sowinski J, Bolanowski M, Ruchala M. GO-QOL--disease-specific quality of life questionnaire in Graves' orbitopathy. Endokrynol Pol. 2015;66(4):362-6. doi: 10.5603/EP.2015.0046.