Sirolimus for Graves' Orbitopathy (GO)

NCT04598815 | Unknown Phase 2

• 1 other identifier: SIRGO
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

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, 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.

Conditions

Graves Ophthalmopathy

Outcome Measures

Primary Outcomes (1)

• GO overall response

  Percentage of subjects with at least two of the following compared to baseline: a) Improvement in 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 Outcomes (18)

• GO overall response

  12 weeks

• GO overall response

  36 weeks

• GO overall response

  48 weeks

• GO relapse

  36 weeks

• GO relapse

  48 weeks

Study Arms (2)

Sirolimus

EXPERIMENTAL

Sirolimus for 12 weeks

Drug: Sirolimus

Methylprendnisolone

EXPERIMENTAL

Methylprednisolone for 12 weeks

Drug: Sirolimus

Interventions

Sirolimus DRUG

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.

Also known as: Rapamycin

Methylprendnisolone; Sirolimus

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients willing and capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
• A diagnosis of Graves' disease based on the presence of hyperthyroidism (either untreated or treated with antithyroid drugs) associated with detectable anti-thyrotropic hormone (TSH) receptor autoantibodies (TRAb). Patients must be euthyroid under control on stable medical regimen and every effort will be made to maintain the euthyroid status for the entire duration of the clinical trial
• 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
• GO duration ≤18 months
• Male and female patients of age: 18-75 years
• Creatinine values within the reference range
• Indexes of liver function (AST, ALT, γGT, alkaline phosphatase, total and direct bilirubin) within the normal range
• Normal blood count, absence of diseases of hematopoiesis
• Women of childbearing potential (WOCBP, namely not in menopause or in menopause since less than two years; in all other instances women will be considered as non-WOCBP) and men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year (as indicated in Appendix) for at least 6 and 7,5 months, respectively, after the last dose of the investigational drug (see also 2014\_09\_HMA\_CTFG\_Contraception.pdf, namely the "2014 CTFG Reccommendtions related to contraception and pregnancy testing in clinical trials")
• Compliant patients, regular follow-up possible

You may not qualify if:

• Optic neuropathy
• Treatment with glucocorticoids, other immunosuppressive drugs or selenium for the last three months
• Previous surgery or radiotherapy for GO
• Radioiodine treatment for hyperthyroidism over the last 3 months, as it can affect GO
• Contraindications to Sirolimus: hypersensitivity to the active substance or to any of the excipients; use of medications interfering with the pharmacokinetic and/or pharmacodynamic properties of rapamycin (e.g. CYP3A4 inhibitors or inducers; see "prohibited therapies")
• Contraindications to GC: hypersensitivity to the active substance or to any of the excipients; uncontrolled hypertension, uncontrolled diabetes; history of peptic ulcer; urinary infections, glaucoma, systemic fungal infections, systemic infections unless appropriate therapy is employed, idiopathic thrombocytopenic purpura, cerebral edema associated with malaria.
• Use of medications interfering with GC or increasing the risk of GC-related adverse events (see prohibited therapies)
• Pregnant or lactating females as determined by positive serum or urine HCG test at baseline
• Acute or chronic liver disease
• Relevant malignancies
• Current and/or previous diseases of hematopoiesis
• Recent (≤1 year) history of alcoholism or drug abuse
• Mental illness that prevent patients from comprehensive, written informed consent

Sponsors & Collaborators

• University of Pisa: lead

Study Sites (1)

Ospedale Cisanello-Endocrinology II

Pisa, 56124, Italy

Location

MeSH Terms

Conditions

Graves Ophthalmopathy

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Central Study Contacts

Michele Marinò, MD

CONTACT

+39050997346; michele.marino@med.unipi.it

Giulia Lanzolla, MD

CONTACT

+393407685085; giulia.lanzolla8@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: October 16, 2020
• First Posted: October 22, 2020
• Study Start: June 1, 2023
• Primary Completion: May 31, 2024
• Study Completion: May 31, 2025
• Last Updated: March 15, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)