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.