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

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

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.

Inclusion Criteria:

1. 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

2. No major treatments for hyperthyroidism (thyroidectomy or radioiodine) in the last 3 months

3. Euthyroidism on anti-thyroid medications or L'thyroxine (LT4) since at least 2 months

4. GO symptoms lasting since no more than one year

5. Active GO: CAS ≥ 3 out of 7 (worst eye)

6. 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

7. No corticosteroids or immunosuppressive treatment for GO in the last 3 months

8. No contraindication to OR: diabetes, hypertension, retinopathy of any type, glaucoma

9. Male and female patients of age: 35-75 years

10. Effective method of contraception during the whole trial and at least six weeks after last intake of trial drugs (only female of reproducing age)

11. No mental illness that prevent patients from comprehensive, written informed consent

12. Compliant patient, regular follow-up possible

Exclusion Criteria:

1. Absence of Graves' hyperthyroidism (present or past)
2. Thyroidectomy or radioiodine in the last 3 months
3. Uncontrolled hyperthyroidism or hypothyroidism
4. GO symptoms lasting since more than one year
5. CAS <3 (worst eye)
6. Optic neuropathy
7. Contraindications to OR (diabetes, retinopathy of any kind)
8. Pregnancy, breast-feeding women
9. No informed consent
10. Acute or chronic liver disease
11. Relevant Malignancy
12. Chronic renal failure or other diseases of any relevance to prevent steroid treatment 13) Corticosteroids or other immunosuppressive agents within last 3 months
13. Recent (≤1 year) history of alcoholism or drug abuse
14. Previous orbital disease other than GO, eye injuries or surgery