Sirolimus in Graves' Orbitopathy (RETROSIRGO)

An Observational, Retrospective, Single-center, Clinical Study to Evaluate the Efficacy of Sirolimus (Rapamycin) in Patients With Graves' Disease and Moderate-to-severe and Active 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 standard treatment, observational study is to evaluate the efficacy of Sirolimus as a second-line treatment in patients with moderately severe, active GO.

Study Overview

• Status: Completed
• Conditions: Graves Ophthalmopathy
• Intervention / Treatment: Drug: Sirolimus; Drug: Methylprednisolone

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 Type: Observational
• Enrollment (Actual): 30

Contacts and Locations

Study Locations

• Italy
  • PI
    • Pisa, PI, Italy, 56124
      • Endocrinologia II

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Consecutive patients with moderate-to-severe, active Graves' orbitopathy treated with either sirolimus of methyprednisolone as a second-line treatment after a previous course of methyprednisolone, over 18 consecutive months

Description

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 Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Sirolimus; Treatment with sirolimus for 12 weeks, given as a second-line treatment	Drug: Sirolimus; 2 mg orally on the first day followed by 0.5 mg per day for 12 weeks
Methylprednisolone; Treatment with methylprednisolone for 12 weeks, given as a second-line treatment	Drug: Methylprednisolone; 500 mg/weekly (6 weeks) intravenously, 250 mg/weekly (6 weeks) (cumulative dose 4.5 g).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
GO overall response	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.	24 weeks

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Pisa

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2020
• Primary Completion (Actual): June 15, 2021
• Study Completion (Actual): June 15, 2021

Study Registration Dates

• First Submitted: April 19, 2022
• First Submitted That Met QC Criteria: April 19, 2022
• First Posted (Actual): April 25, 2022

Study Record Updates

• Last Update Posted (Actual): April 25, 2022
• Last Update Submitted That Met QC Criteria: April 19, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Genetic Diseases, Inborn; Thyroid Diseases; Eye Diseases, Hereditary; Graves Disease; Exophthalmos; Orbital Diseases; Goiter; Hyperthyroidism; Eye Diseases; Graves Ophthalmopathy; Physiological Effects of Drugs; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Sirolimus
• Other Study ID Numbers: RETROSIRGO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No