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

Thyroid Associated Ophthalmopathy Clinical Trial

— ORGO  

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03098225
• Other study ID #: ORGO
• Status: Not yet recruiting
• Phase: Phase 4
• Start date: January 1, 2024
• Est. completion date: March 31, 2027

Study information

• Verified date: March 2023
• Source: University of Pisa
• Contact: Michele Marinò, MD
• Phone: +39-348-0616959
• Email: michele.marino[@]med.unipi.it
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 120
• Est. completion date: March 31, 2027
• Est. primary completion date: March 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 35 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Eye Diseases
• Graves Ophthalmopathy
• Thyroid Associated Ophthalmopathy

Intervention

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.

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.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University of Pisa

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Comparison of overall GO outcome determined using a composite evaluation	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)	52 weeks
Secondary	Comparison of overall GO outcome determined using a composite evaluation	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)	26 weeks
Secondary	Comparison of a disease specific quality of life questionnaire (GO-QoL)	Comparison of a disease specific quality of life questionnaire (GO-QoL)	26 weeks
Secondary	GO relapse	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)	52 weeks
Secondary	Comparison of a disease specific quality of life questionnaire (GO-QoL)	Comparison of a disease specific quality of life questionnaire (GO-QoL)	52 weeks