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

Primary Purpose

Thyroid Associated Ophthalmopathy

Status
Not yet recruiting
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Orbital radiotherapy
Methylprednisolone
Sponsored by
University of Pisa
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Thyroid Associated Ophthalmopathy

Eligibility Criteria

35 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Active Comparator

    Arm Label

    Radiotherapy

    No Radiotherapy

    Arm Description

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

    Patients with moderately severe GO treated with Intravenous glucocorticoids alone

    Outcomes

    Primary Outcome Measures

    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)

    Secondary Outcome Measures

    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)
    Comparison of a disease specific quality of life questionnaire (GO-QoL)
    Comparison of a disease specific quality of life questionnaire (GO-QoL)
    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)
    Comparison of a disease specific quality of life questionnaire (GO-QoL)
    Comparison of a disease specific quality of life questionnaire (GO-QoL)

    Full Information

    First Posted
    March 21, 2017
    Last Updated
    March 14, 2023
    Sponsor
    University of Pisa
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    1. Study Identification

    Unique Protocol Identification Number
    NCT03098225
    Brief Title
    A Trial to Evaluate the Efficacy of Orbital Radiotherapy in Graves' Orbitopathy
    Acronym
    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
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    March 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    January 1, 2024 (Anticipated)
    Primary Completion Date
    March 31, 2026 (Anticipated)
    Study Completion Date
    March 31, 2027 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Principal Investigator
    Name of the Sponsor
    University of Pisa

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Product Manufactured in and Exported from the U.S.
    No
    Data Monitoring Committee
    No

    5. 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.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Thyroid Associated Ophthalmopathy

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 4
    Interventional Study Model
    Parallel Assignment
    Masking
    Investigator
    Masking Description
    Ophthalmology blinded to treatment
    Allocation
    Randomized
    Enrollment
    120 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Radiotherapy
    Arm Type
    Experimental
    Arm Description
    Patients with moderately severe GO treated with Intravenous glucocorticoids associated with orbital radiotherapy
    Arm Title
    No Radiotherapy
    Arm Type
    Active Comparator
    Arm Description
    Patients with moderately severe GO treated with Intravenous glucocorticoids alone
    Intervention Type
    Radiation
    Intervention Name(s)
    Orbital radiotherapy
    Other Intervention Name(s)
    OR
    Intervention Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    Methylprednisolone
    Other Intervention Name(s)
    ivGC
    Intervention Description
    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.
    Primary Outcome Measure Information:
    Title
    Comparison of overall GO outcome determined using a composite evaluation
    Description
    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)
    Time Frame
    52 weeks
    Secondary Outcome Measure Information:
    Title
    Comparison of overall GO outcome determined using a composite evaluation
    Description
    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)
    Time Frame
    26 weeks
    Title
    Comparison of a disease specific quality of life questionnaire (GO-QoL)
    Description
    Comparison of a disease specific quality of life questionnaire (GO-QoL)
    Time Frame
    26 weeks
    Title
    GO relapse
    Description
    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)
    Time Frame
    52 weeks
    Title
    Comparison of a disease specific quality of life questionnaire (GO-QoL)
    Description
    Comparison of a disease specific quality of life questionnaire (GO-QoL)
    Time Frame
    52 weeks

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    35 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    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 13) Corticosteroids or other immunosuppressive agents within last 3 months Recent (≤1 year) history of alcoholism or drug abuse Previous orbital disease other than GO, eye injuries or surgery
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Michele Marinò, MD
    Phone
    +39-348-0616959
    Email
    michele.marino@med.unipi.it
    First Name & Middle Initial & Last Name or Official Title & Degree
    Marenza Leo, MD
    Phone
    +39-389-7993873
    Email
    marenzaleo@libero.it

    12. IPD Sharing Statement

    Plan to Share IPD
    No

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

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