Sirolimus for Graves' Orbitopathy (GO)
Sirolimus for Graves' Orbitopathy (GO)
Graves' Orbitopathy (GO) is a disabling and disfiguring condition associated with Graves'
 Disease, due to autoimmunity against antigens expressed by the thyroid and orbital tissues,
 and resulting in orbital fibroblast proliferation and release of glycosaminoglycans. The
 current treatments available, especially glucocorticoids, are not effective in all patients.
 Two cases of patients with GO treated with Sirolimus have been reported with an excellent
 response to the drug.

 The rationale for the use of Sirolimus lies in its mechanisms of action. Sirolimus is able to
 inhibit T-cell activation as well as fibroblast proliferation. In addition, acts indirectly
 on the Insulin-Like Growth Factor-1 (IGF-1) pathway, and recent clinical trials have shown
 that a monoclonal antibody against the IGF-1 receptor (Teprotumumab) is effective in patients
 with GO. Thus, Sirolimus could be used in GO as monotherapy in patients with GO.

 The aim of the present drug vs placebo, double-blind, randomized clinical trial is to
 evaluate the efficacy of Sirolimus in patients with moderately severe, active GO. 54 patients
 (27 per group) will be randomized into two groups, A and B. Patients in group A will receive
 Sirolimus for 12 weeks, followed by a 12-week wash-out period, and by a 12-week follow-up
 period. Patients in group B will receive placebo for 12 weeks, followed by a 12-week wash-out
 period, and by a 12-week treatment with Sirolimus. The primary objective of the study is the
 reduction of proptosis after 12 weeks of treatment. The secondary objectives are: 1)
 reduction of proptosis at 24 and 36 weeks; 2) overall response of GO at 12, 24 and 36 weeks:
 3) reduction of the GO clinical activity score (CAS) at 12, 24 and 36 weeks, and 4)
 Improvement in the quality of life at 12, 24 and 36 weeks.
Inclusion Criteria:

 1. Patients willing and capable of giving written informed consent, which includes
 compliance with the requirements and restrictions listed in the consent form

 2. A diagnosis of Graves' disease based on the presence of hyperthyroidism (either
 untreated or treated with antithyroid drugs) associated with detectable
 anti-thyrotropic hormone (TSH) receptor autoantibodies (TRAb). Patients must be
 euthyroid under control on stable medical regimen and every effort will be made to
 maintain the euthyroid status for the entire duration of the clinical trial

 3. A moderate-to-severe GO, defined as the presence of at least one of the following
 criteria: an exophthalmos ≥2 mm compared with normal values for sex and race; presence
 of inconstant to constant diplopia; a lid retraction ≥2 mm

 4. Active GO: CAS (4) ≥ 3 out of 7 points in the most affected eye

 5. Male and female patients of age: 18-75 years

 6. Creatinine values within the reference range

 7. Indexes of liver function: aspartate aminotransferase (AST), alanine aminotransferase
 (ALT), Gamma-glutamyl transferase (γGT), alkaline phosphatase, total and direct
 bilirubin) within the normal range

 8. Normal blood count, absence of diseases of hematopoiesis

 9. Women of childbearing potential (WOCBP, namely not in menopause or in menopause since
 less than two years; in all other instances women will be considered as non-WOCBP) and
 men who are sexually active with WOCBP must use any contraceptive method with a
 failure rate of less than 1% per year (as indicated in Appendix) for at least 6 and
 7,5 months, respectively, after the last dose of the investigational drug (see also
 2014_09_Heads of Medicines Agencies (HMA)_Clinical Trial Facilitation Group
 (CTFG)_Contraception.pdf, namely the "2014 CTFG Reccommendations related to
 contraception and pregnancy testing in clinical trials")

 10. Compliant patients, regular follow-up possible

 Exclusion Criteria:

 1. Optic neuropathy

 2. Treatment with glucocorticoids, other immunosuppressive drugs or selenium for the last
 three months

 3. Contraindications to Sirolimus: hypersensitivity to the active substance or to any of
 the excipients; use of medications interfering with the pharmacokinetic and/or
 pharmacodynamic properties of rapamycin (e.g. CYP3A4 inhibitors or inducers; see
 "prohibited therapies")

 4. Pregnant or lactating females as determined by positive serum or urine human chorionic
 gonadotropin (HCG) test at baseline

 5. Acute or chronic liver disease

 6. Relevant malignancies

 7. Current and/or previous diseases of hematopoiesis

 8. Recent (≤1 year) history of alcoholism or drug abuse

 9. Mental illness that prevent patients from comprehensive, written informed consent