Tocilizumab in Corticosteroid-Resistant Graves' Orbitopathy (Thyroid Eye Disease)

NCT06367517 | Recruiting

• 1 other identifier: KB/114/2022
• Study Type: observational
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Orbitopathy, Graves; Thyroid Eye Disease; Ophthalmopathy

Keywords

Graves' disease; Graves' orbitopathy; Tocilizumab; Thyroid Eye Disease; Hyperthyroidism

Outcome Measures

Primary Outcomes (2)

• Disease improvement

  Proportion of patients improved at 16, 24 and 48 weeks as assessed by a composite ophthalmic score. A response to treatment will be considered positive in the case of an improvement of at least 2 of the following features in 1 eye, without concomitant deterioration in the other eye: * decrease in eyelid aperture by at least 2 mm measured with a ruler * decrease in proptosis by at least 2 mm measured with Hertel Exophthalmometer * increase in eyelid motility by at least 8° assessed by ophthalmologist or improvement of Bahn-Gorman diplopia score (Grade I - intermittent diplopia, Grade II - Inconstant diplopia, Grade III - Constant diplopia) * decrease in 7-item (spontaneous retrobulbar pain, pain on attempted upward or downward gaze, redness of eyelids, redness of conjunctiva, sweeling of caruncle or plica, swelling of eyelids, swelling of conjunctiva) clinical activity score (CAS) by at least 2 points.

  at 16, 24 and 48 weeks

• Improvement of quality of life

  Improvement of quality of life according to the disease-specific quality of life questionnaire in Graves' orbitopathy (GO-QoL) at 16, 24 and 48 weeks. All Go-QoL questions will be scored as 'severely limited' (one point), a 'little limited' (two points), or 'not limited at all' (three points). The questions will be transformed from 0 to 100 by the following formula: total score= (raw score- 8)/16 x100. An improvement in QoL wil be considered, if there will be an increase of 6 or more points on either one (or both) the GO-QoL scales (functioning and appearance);

  at 16, 24 and 48 weeks

Secondary Outcomes (8)

• Disease inactivation

  at 16, 24 and 48 weeks

• Proportion of patients achieving response in specific GO signs and symptoms

  at 16, 24 and 48 weeks

• Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

  from 0 to 16 weeks

• Decrease in concentration of thyrotropin receptor antibodies

  at 4, 8, 12, 16, 24 and 48 weeks

• Decrease in levels of proinflammatory cytokines

  at 4, 8, 12, 16, 24 and 48 weeks

Study Arms (1)

Graves' orbitopathy

Patients with active, moderate to severe TED, without disease improvement after methylprednisolone pulse therapy in an intermediate-dose schedule (starting dose of 0.5 g once weekly for 6 weeks, followed by 0.25 g once weekly for 6 weeks) or high-dose regimens (a starting dose of 0.75 g once weekly for 6 weeks, followed by 0.5 g once weekly for 6 weeks) with or without concomitant radiotherapy.

Drug: Tocilizumab

Interventions

Tocilizumab DRUG

Tocilizumab administrated at a dose of 8 mg/kg, given once every four weeks

Also known as: RoActemra

Graves' orbitopathy

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Medical University of Warsaw: lead

Study Sites (1)

Department of Internal Medicine and Endocrinology, Medical University of Warsaw

Warsaw, 02-097, Poland

RECRUITING

Related Publications (5)

• 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.

  PMID: 36480280 BACKGROUND

• 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.

  PMID: 30081019 BACKGROUND

• 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.

  PMID: 38497401 BACKGROUND

• 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.

  PMID: 34297684 BACKGROUND

• 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.

  PMID: 26323474 BACKGROUND

MeSH Terms

Conditions

Graves Ophthalmopathy; Eye Diseases; Graves Disease; Hyperthyroidism

Interventions

tocilizumab

Condition Hierarchy (Ancestors)

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

Study Officials

• Tomasz Bednarczuk, MD, PHD

  Medical University of Warsaw

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Tomasz Bednarczuk, MD, PHD

CONTACT

48225992975; tomasz.bednarczuk@wum.edu.pl

Joanna Rymuza, MD, PHD

CONTACT

48225992975; joanna.rymuza@wum.edu.pl

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof

Study Record Dates

• First Submitted: March 27, 2024
• First Posted: April 16, 2024
• Study Start: May 20, 2021
• Primary Completion: May 20, 2025
• Study Completion (Estimated): May 20, 2026
• Last Updated: April 16, 2024

Record last verified: 2024-04

Locations

PL (1)