NCT04598815

Sirolimus for Graves' Orbitopathy (GO)

A Phase II, Randomized, Superiority, Adaptive, Open-label, Single-center, Clinical Trial to Evaluate the Efficacy of Sirolimus (Rapamycin) in Patients With Graves' Disease and Moderate-to-severe and Active Graves' Orbitopathy (GO)

• Status: Unknown
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 54 (estimated)
• Sponsor: University of Pisa · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

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 standard treatment, open-label, 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. Patients in group B will receive methylprendnisolone for 12 weeks. The primary objective of the study is the response of GO at 24 weeks based on a composite evaluation. The secondary Objectives will be: 1) the response of of GO at 12, 36 and 48 weeks; 2) Relapse of GO at 36 and 48 weeks (worsening compared with the 24-week evaluation); 3) The reduction of proptosis at 12, 24, 36 and 48 weeks (proportion of patients with a reduction of proptosis of at least 2 mm); 4) Reduction of the GO clinical activity score (CAS) at 12, 24, 36 and 48 weeks; 5) Quality of life (Qol) at 12, 24, 36 and 48 weeks. The safety objectives will be adverse events, adverse drug reactions, unexpected adverse reaction, suspected unexpected adverse reactions and death, across the study and at 12, 24, 36 and 48 weeks.

Detailed description

Study Design Phase II, randomized, adaptive, superiority, open-label, single-center, pilot clinical trial. Fifty-four patients with moderate-to-severe and active GO will be randomized into two intervention groups, A and B, with a ratio of 1: 1. Subjects assigned to group A will receive Sirolimus for 12 weeks. Patients assigned to group B will receive a cumulative dose of 4.5 g of methylprednisolone divided into 12 weekly infusions. This treatment scheme is the clinical standard and patients would be treated with methylprednisolone in any case, even if they did not accept to participate to the study. Enrollment duration: 24 months Study duration: 36 months Tentative start of trial: July 1st 2022 Study Population Fifty-four patients with Graves' disease and GO will be recruited during the routine clinical activity carried out at the Endocrinology Unit II of AOUP, which is a tertiary referral center for thyroid diseases. Study Timeline * Screening visit (2-6 weeks before the first visit) * 1st (baseline) visit - (Time 0): randomization and administration of the first dose of trial agent * Treatment period (week 1-week 12): daily administration of the trial agent (Sirolimus) or weekly administration of the standard treatment (methylprednisolone) * Methylprednisolone treatment period and treatment visits (week 2-week 13); weekly methylprednisolone administrations (week 2-week 13) * Safety visits (week 3, 5, 7, 9, 11) * 2nd visit (week 12) * 3rd visit (week 24) * 4th visit (week 36) * 5th visit (week 48)

Conditions

• Graves Ophthalmopathy

Interventions

Type	Name	Description
DRUG	Sirolimus	Group Sirolimus: Patients will receive a first dose of Sirolimus of one 2 mg tablet on the first day, given approximately at 10 am, followed by 0.5 mg tablet per day for 12 weeks. Group Methylprednisolone: Methylprednisolone pulse therapy will be administered for 12 weeks as follows: 500 mg iv once weekly for 6 weeks, then 250 mg iv once weekly for a further 6 weeks, for a cumulative dose 4.5 g.

Timeline

• Start date: 2023-06-01
• Primary completion: 2024-05-31
• Completion: 2025-05-31
• First posted: 2020-10-22
• Last updated: 2023-03-15

Locations

1 site across 1 country: Italy