Sirolimus in Graves' Orbitopathy

Completed

• Conditions: Graves Ophthalmopathy
• Interventions: Drug: Sirolimus; Drug: Methylprednisolone

• Registration Number: NCT05345119
• Lead Sponsor: University of Pisa

Brief 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, observational study is to evaluate the efficacy of Sirolimus as a second-line treatment in patients with moderately severe, active GO.

Detailed Description

Study Design: observational

Thirty consecutive patients with moderate-to-severe and active GO treated with sirolimus (15 patients) or methylprednisolone (15 patients) observance 18 consecutive months will be compared.

Study Timeline

Baseline visit - (Time 0) Treatment period (week 1-week 12): daily administration of the trial agent (Sirolimus) or weekly administration of the standard treatment (methylprednisolone) Outcome visit (week 24)

Study Timeline

• Study Start: 2020-01-15
• Primary Completion: 2021-06-15
• Study Completion: 2021-06-15
• Status Verified: 2022-04
• Study First Submitted: 2022-04-19
• Study First Submitted QC: 2022-04-19
• Last Update Submitted: 2022-04-19
• Study First Posted: 2022-04-25
• Last Update Posted: 2022-04-25

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

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 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
3. Active GO: CAS (4) ≥2 out of 7 points in the most affected eye
4. Previous GO treatment with glucocorticoids and/or orbital radiotherapy and/or orbital decompressive surgery, performed more than 24 weeks before the current treatment
5. Male and female patients of age: 18-75 years

Exclusion Criteria

1. Optic neuropathy
2. Treatment with glucocorticoids or other immunosuppressive medications, and/or selenium, and/or orbital radiotherapy and/or orbital decompressive surgery in the 24 weeks preceding the current treatment
3. Mental illness that prevents patients from comprehensive, written informed consent

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Sirolimus	Sirolimus	Treatment with sirolimus for 12 weeks, given as a second-line treatment
Methylprednisolone	Methylprednisolone	Treatment with methylprednisolone for 12 weeks, given as a second-line treatment

Primary Outcome Measures

Name	Time	Method
GO overall response	24 weeks	Percentage of subjects with at least two of the following compared to baseline: a) Improvement in clinical activity score (CAS) by at least 1 point ; b) Improvement in exophthalmos by at least 2 mm; c) Improvement in lid aperture by at least 2 mm; d) Improvement in eye muscle ductions ≥8 degrees; e) Improvement of visual acuity by at least 0.2/1, without worsening of any of these parameters in the contralateral eye if applicable.

Secondary Outcome Measures

Name	Time	Method
Change in exophthalmos	24 weeks	Percentage of subjects with a reduction greater than or equal to 2 mm compared with the baseline evaluation in the study eye, without worsening in the contralateral eye
Change in the clinical activity score (CAS)	24 weeks	Percentage of subjects with a reduction of CAS by at least two points in the study eye, without worsening in the contralateral eye
Change in quality of life	24 weeks	Comparison of the quality of life scores between the two groups, determined with a questionnaire specific for GO (GO-QoL)
Change in eye ductions	24 weeks	Percentage of subjects with an increase in eye ductions at least 8 degrees
Change in eyelid aperture	24 weeks	Percentage of subjects with a reduction greater than or equal to 2 mm
Change in diplopia	24 weeks	Percentage with an improvement in diplopia

Trial Locations

Locations (1)

Endocrinologia II; 🇮🇹 Pisa, PI, Italy