ORGO: A Trial to Evaluate the Efficacy of Orbital Radiotherapy in Graves' Orbitopathy

Sponsor

University of Pisa (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT03098225

Collaborator

(none)

120

Enrollment

Arms

38.9

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

Graves' orbitopathy (GO) is a disfiguring and disabling disease that profoundly impairs the quality of life of affected patients. High dose intravenous (iv) glucocorticoids (GC) (ivGC) is a well established, widely used treatment for active GO. The use of systemic glucocorticoids takes advantage from their immune suppressive and antiinflammatory actions, resulting in an overall beneficial effect ranging from ~35 to ~60% of patients in various studies. The intravenous route of administration has been shown to be superior to the oral route, both in terms of GO outcome and side effect profile. The combination of ivGC and orbital radiotherapy (OR) is used routinely in patients with moderate-severe, active GO, as a second-line treatment, as also recommended in the recent Guidelines published by the European Thyroid Association/European Group on Graves' Orbitopathy. Thus, the majority of studies have shown that OR increases the response rate to GC. Those studies were performed using oral GC, whereas it is not known whether OR potentiate also the effects of ivGC.

The present study is aimed at determining whether OR potentiate the effects of ivGC in the treatment of moderately severe and active GO, in terms of GO outcome and quality of life. A possible extension of the study can be foreseen, aimed at investigating the very long time GO outcome.

Condition or Disease	Intervention/Treatment	Phase
Thyroid Associated Ophthalmopathy	Radiation: Orbital radiotherapy Drug: Methylprednisolone	Phase 4

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Investigator)

Masking Description:

Ophthalmology blinded to treatment

Primary Purpose:

Treatment

Official Title:

A Phase IV, Randomized, Multi-center Clinical Trial to Compare the Efficacy of Orbital Radiotherapy in Association With Intravenous Glucocorticoids vs Intravenous Glucocorticoids Alone for Moderately Severe and Active Graves' Orbitopathy

Anticipated Study Start Date :

Jan 1, 2021

Anticipated Primary Completion Date :

Mar 31, 2024

Anticipated Study Completion Date :

Mar 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Radiotherapy Patients with moderately severe GO treated with Intravenous glucocorticoids associated with orbital radiotherapy	Radiation: Orbital radiotherapy A high-voltage linear accelerator will be used and a cumulative radiation dose of 20 Gy will be delivered to each eye in 10 fractionated doses over a period of 2 weeks. All patients will be treated in both eyes. Other Names: OR Drug: Methylprednisolone Methylprednisolone pulse therapy for 12 weeks as follows: 500 mg IV once weekly for 6 weeks, then 250 mg IV once weekly for a further 6 weeks. Cumulative dose 4.5 g. Other Names: ivGC
Active Comparator: No Radiotherapy Patients with moderately severe GO treated with Intravenous glucocorticoids alone	Drug: Methylprednisolone Methylprednisolone pulse therapy for 12 weeks as follows: 500 mg IV once weekly for 6 weeks, then 250 mg IV once weekly for a further 6 weeks. Cumulative dose 4.5 g. Other Names: ivGC

Arm

Intervention/Treatment

Experimental: Radiotherapy

Patients with moderately severe GO treated with Intravenous glucocorticoids associated with orbital radiotherapy

Radiation: Orbital radiotherapy

A high-voltage linear accelerator will be used and a cumulative radiation dose of 20 Gy will be delivered to each eye in 10 fractionated doses over a period of 2 weeks. All patients will be treated in both eyes.

Other Names:

Drug: Methylprednisolone

Methylprednisolone pulse therapy for 12 weeks as follows: 500 mg IV once weekly for 6 weeks, then 250 mg IV once weekly for a further 6 weeks. Cumulative dose 4.5 g.

Other Names:

ivGC

Active Comparator: No Radiotherapy

Patients with moderately severe GO treated with Intravenous glucocorticoids alone

Drug: Methylprednisolone

Methylprednisolone pulse therapy for 12 weeks as follows: 500 mg IV once weekly for 6 weeks, then 250 mg IV once weekly for a further 6 weeks. Cumulative dose 4.5 g.

Other Names:

ivGC

Outcome Measures

Primary Outcome Measures

Comparison of overall GO outcome determined using a composite evaluation [52 weeks]
A composite evaluation of GO was described previously. Improvement is defined as amelioration of two parameters in at least one eye, without deterioration of any parameters in both eyes: Deterioration is defined as worsening in two parameters in at least one eye: All other cases are defined as "no change" The parameters are: Eyelid swelling (improvement/worsening according to EUGOGO Atlas evaluation) Lid aperture in mm (significant variation: 2 or more mm) Clinical activity score (CAS) (7 items: spontaneous pain, evoked pain, eyelid edema, eyelid redness, conjunctiva redness, caruncle edema, chemosis; significant change: at least 2 points) Exophthalmos in mm (significant variation 2 or more mm) Eye muscle involvement - diplopia score (Gorman score) (significant variation: disappearance or change in the degree, or improvement of ≥12 degrees in motility)

Secondary Outcome Measures

Comparison of overall GO outcome determined using a composite evaluation [26 weeks]
A composite evaluation of GO was described previously. Improvement is defined as amelioration of two parameters in at least one eye, without deterioration of any parameters in both eyes: Deterioration is defined as worsening in two parameters in at least one eye: All other cases are defined as "no change" The parameters are: Eyelid swelling (improvement/worsening according to EUGOGO Atlas evaluation) Lid aperture in mm (significant variation: 2 or more mm) Clinical activity score (CAS) (7 items: spontaneous pain, evoked pain, eyelid edema, eyelid redness, conjunctiva redness, caruncle edema, chemosis; significant change: at least 2 points) Exophthalmos in mm (significant variation 2 or more mm) Eye muscle involvement - diplopia score (Gorman score) (significant variation: disappearance or change in the degree, or improvement of ≥12 degrees in motility)
Comparison of a disease specific quality of life questionnaire (GO-QoL) [26 weeks]
Comparison of a disease specific quality of life questionnaire (GO-QoL)
GO relapse [52 weeks]
GO worsening in comparison with the 26 week evaluation, by a composite GO score: Worsening is defined as worsening in two parameters in at least one eye: The parameters are: Eyelid swelling (worsening according to EUGOGO Atlas evaluation) Lid aperture in mm (significant worsening: 2 or more mm) Clinical activity score (CAS) (7 items: spontaneous pain, evoked pain, eyelid edema, eyelid redness, conjunctiva redness, caruncle edema, chemosis; significant worsening: at least 2 points) Exophthalmos in mm (significant worsening: 2 or more mm) Eye muscle involvement - diplopia score (Gorman score) (significant worsening: appearance or change in the degree, or worsening of ≥12 degrees in motility)
Comparison of a disease specific quality of life questionnaire (GO-QoL) [52 weeks]
Comparison of a disease specific quality of life questionnaire (GO-QoL)

Eligibility Criteria

Criteria

Ages Eligible for Study:

35 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

A diagnosis of Graves' disease based on the presence of hyperthyroidism (either untreated or treated with antithyroid drugs) associated with detectable anti-TSH receptor autoantibodies
No major treatments for hyperthyroidism (thyroidectomy or radioiodine) in the last 3 months
Euthyroidism on anti-thyroid medications or L'thyroxine (LT4) since at least 2 months
GO symptoms lasting since no more than one year
Active GO: CAS ≥ 3 out of 7 (worst eye)
Moderate or moderately severe GO: at least one of the following signs (worst eye):

Exophthalmos ≥ 22 mm
Eye muscle involvement with mono-ocular ductions in any direction of gaze of less than 30° or evident dismotility
Diplopia according to Gorman score of grades a-c

No corticosteroids or immunosuppressive treatment for GO in the last 3 months
No contraindication to OR: diabetes, hypertension, retinopathy of any type, glaucoma
Male and female patients of age: 35-75 years
Effective method of contraception during the whole trial and at least six weeks after last intake of trial drugs (only female of reproducing age)
No mental illness that prevent patients from comprehensive, written informed consent
Compliant patient, regular follow-up possible

Exclusion Criteria:

Absence of Graves' hyperthyroidism (present or past)
Thyroidectomy or radioiodine in the last 3 months
Uncontrolled hyperthyroidism or hypothyroidism
GO symptoms lasting since more than one year
CAS <3 (worst eye)
Optic neuropathy
Contraindications to OR (diabetes, retinopathy of any kind)
Pregnancy, breast-feeding women
No informed consent
Acute or chronic liver disease
Relevant Malignancy
Chronic renal failure or other diseases of any relevance to prevent steroid treatment