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NCT Number: NCT05345119

Sirolimus in Graves' Orbitopathy

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.

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Key information

Conditions

Graves Ophthalmopathy Autoimmune Diseases Congenital, Hereditary, and Neonatal Diseases and Abnormalities Endocrine System Diseases Exophthalmos Eye Diseases Eye Diseases, Hereditary Genetic Diseases, Inborn Goiter Graves Disease Hyperthyroidism Immune System Diseases Orbital Diseases Thyroid Diseases

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Observational

Primary location

Endocrinologia II

Pisa, PI, 56124, Italy

About this study

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)

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Patients willing and capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
  • 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
  • Active GO: CAS (4) ≥2 out of 7 points in the most affected eye
  • Previous GO treatment with glucocorticoids and/or orbital radiotherapy and/or orbital decompressive surgery, performed more than 24 weeks before the current treatment
  • Male and female patients of age: 18-75 years

Exclusion criteria

  • Optic neuropathy
  • 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
  • Mental illness that prevents patients from comprehensive, written informed consent

Treatment and study plan

sirolimus

Drug

2 mg orally on the first day followed by 0.5 mg per day for 12 weeks

methylprednisolone

Drug

500 mg/weekly (6 weeks) intravenously, 250 mg/weekly (6 weeks) (cumulative dose 4.5 g).

Primary outcomes

  1. GO overall response

    Time frame: 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 outcomes

  1. Change in exophthalmos

    Time frame: 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

  2. Change in the clinical activity score (CAS)

    Time frame: 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

  3. Change in quality of life

    Time frame: 24 weeks

    Comparison of the quality of life scores between the two groups, determined with a questionnaire specific for GO (GO-QoL)

  4. Change in eye ductions

    Time frame: 24 weeks

    Percentage of subjects with an increase in eye ductions at least 8 degrees

  5. Change in eyelid aperture

    Time frame: 24 weeks

    Percentage of subjects with a reduction greater than or equal to 2 mm

  6. Change in diplopia

    Time frame: 24 weeks

    Percentage with an improvement in diplopia

Sponsors and collaborators

Lead sponsor

University of Pisa

Other

Registry information

Official study title

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)

Acronym: RETROSIRGO

Important dates

Study start
2020
Primary completion
2021
Study completion
2021
First posted
Apr 25, 2022
Registry last updated
Apr 25, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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