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

Inclusion Criteria:

• Written informed consent

• Male or female, 18-80 years old

• Patients with active (Clinical Activity Score ≥ 3 in 7-item scale) andmoderate-to-severe GO, diagnosed according to the EUGOGO guidelines, after thecompletion 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% ofnormal range) on either anti-thyroid medications (tyonamides) to controlhyperthyroidism 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 toprevent pregnancy during the study period, and at least during a period of sixmonths 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 thestudy

• Patients who could need treatment with radioactive iodine or thyroidectomy duringthe study

• Treatment with any biological therapy at any time.

• Active infection.

• History of recurrent clinically significant infection or recurrent bacterialinfections.

• 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 therapyfor a chronic infection, hospitalization for treatment of infection within 60 daysbefore Day 0, use of parenteral antibiotics within 60 days before Day 0, use of oralantibiotics within 30 days before Day 0.

• History of intestinal ulceration or diverticulitis

• Patients with a history of chronic liver disease or liver disorders: Alanineaminotransferase (ALT) and aspartate aminotransferase (AST) above 5 times upperlimit of normal (ULN)

• HBsAg positive test.

• HBcAb positive test, regardless of HBsAb status, will undergo HBV DNA which, ifpositive, will be excluded. HbcAb positive, HbsAg negative patients withundetectable HBV DNA will receive antiviral prophylaxis throughout theimmunosuppressive therapy.

• Hepatitis C antibody positive test at screening.

• Positive test for Human Immunodeficiency Virus (HIV) antibody at screening orhistorically. 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 isacceptable if bilirubin is fractionated and direct bilirubin is<35%).

• Cardiovascular or cerebrovascular disease clinically significant.

• Other serious chronic illness (including uncontrolled diabetes mellitus, renaldisease, 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.