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Effects of Atorvastatin in Graves' Orbitopathy (GO) (STAGO)

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ClinicalTrials.gov Identifier: NCT03110848
Recruitment Status : Not yet recruiting
First Posted : April 12, 2017
Last Update Posted : June 7, 2019
Sponsor:
Information provided by (Responsible Party):
Marinò Michele, University of Pisa

Brief Summary:

Graves' orbitopathy (GO) is the most common extra-thyroidal manifestation of Graves' disease (GD), being observed in ~25% of patients. Besides genetic and demographical variables, risk factors associated with the development of GO in GD patients are known to be inadequate control of hyperthyroidism, radioiodine treatment, and smoking. In a large retrospective study conducted in more than 8,000 individuals with GD it was observed that treatment with 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, better known as statins, is associated with a ~40% reduced risk of developing GO in GD patients. The findings were interpreted as the consequence of the anti-inflammatory action of statins, being GO notoriously an autoimmune, inflammatory conditions.

Statins are widely used for the treatment of hypercholesterolemia, for which they are quite effective. The possibility that their "protective" effect in terms of GO development in GD patients, as observed by Stein et al., was simply due to their hypolipemic actions was not considered. To evaluate the possibility that the findings reflected lowering of cholesterol rather than a direct anti-inflammatory effect of statins a prospective, observational study to assess the association between GO and high cholesterol levels and/or the relationship between the degree and/or activity of GO and hypercholesterolemia is ongoing. Preliminary findings suggest that GO is more severe and active in patients with high cholesterol levels. On the basis of these observations, the present randomized clinical trial was designed to be performed in hypercholesterolemic patients with GD and moderate-to-severe and active GO, aimed at investigating if lowering of cholesterol levels with statins is associated with a better outcome of GO.


Condition or disease Intervention/treatment Phase
Thyroid Associated Ophthalmopathy Hypercholesterolemia Drug: Atorvastatin Drug: Methylprednisolone Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 88 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Investigator)
Masking Description: Ophthalmologist blinded to treatment
Primary Purpose: Treatment
Official Title: A Phase II, Open-labeled, Ophthalmological External Investigator-blinded, Single-center, Randomized, Superiority, Non Profit, Pilot Clinical Trial to Evaluate the Effects of Atorvastatin on Graves' Orbitopathy (GO) in Hypercholesterolemic Patients With Moderate-to-severe and Active GO Subjected to Intravenous Glucocorticoid Therapy: the STAGO Study
Estimated Study Start Date : July 12, 2019
Estimated Primary Completion Date : December 12, 2019
Estimated Study Completion Date : July 12, 2020


Arm Intervention/treatment
Experimental: Statins
Atorvastatin 20 mg daily associated with intravenous glucocorticoids, namely 500 mg of methylprednisolone weekly for 6 weeks, followed by 250 mg weekly for another 6 weeks, for a total dose of 4.5 mg.
Drug: Atorvastatin
Atorvastatin 20 mg daily
Other Name: Statins

Drug: Methylprednisolone
500 mg of methylprednisolone weekly for 6 weeks, followed by 250 mg weekly for another 6 weeks, for a total dose of 4.5 mg.
Other Name: Intravenous glucocorticoids

Active Comparator: No statins
Intravenous glucocorticoids, namely 500 mg of methylprednisolone weekly for 6 weeks, followed by 250 mg weekly for another 6 weeks, for a total dose of 4.5 mg.
Drug: Methylprednisolone
500 mg of methylprednisolone weekly for 6 weeks, followed by 250 mg weekly for another 6 weeks, for a total dose of 4.5 mg.
Other Name: Intravenous glucocorticoids




Primary Outcome Measures :
  1. Overall GO outcome determined using a composite evaluation [ Time Frame: 6 months ]

    Overall GO outcome determined using a composite evaluation.

    A composite evaluation of GO was described previously.

    Possible outcomes are: improvement, worsening, no change, resulting in 3 categorical values

    Improvement: amelioration of two parameters in at least one eye, without deterioration of any parameters in both eyes:

    Deterioration: worsening in two parameters in at least one eye:

    All other cases are "no change"

    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 :
  1. Overall GO outcome determined using a composite evaluation [ Time Frame: 3 months ]

    Overall GO outcome determined using a composite evaluation.

    A composite evaluation of GO was described previously.

    Possible outcomes are: improvement, worsening, no change, resulting in 3 categorical values

    Improvement: amelioration of two parameters in at least one eye, without deterioration of any parameters in both eyes:

    Deterioration: worsening in two parameters in at least one eye:

    All other cases are "no change"

    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)


  2. Comparison of a disease specific quality of life questionnaire (GO-QoL) [ Time Frame: 6 months ]
    A GO-specific quality of life questionnaire (GO-QoL) comprises 16 items, 8 concerning appearance and 8 concerning function. The combination of the various parameters gives a final numeric value which will be compared between the two groups

  3. Comparison of a disease specific quality of life questionnaire (GO-QoL) [ Time Frame: 3 months ]
    A GO-specific quality of life questionnaire (GO-QoL) comprises 16 items, 8 concerning appearance and 8 concerning function. The combination of the various parameters gives a final numeric value which will be compared between the two groups

  4. GO relapse [ Time Frame: 6 months ]
    Worsening in comparison with the 3-month evaluation

  5. Requirement for additional treatments [ Time Frame: 3 months ]
    Additional intravenous glucocorticoids, radiotherapy, orbital decompression, immunosuppressive treatments of any kind

  6. Requirement for additional treatments [ Time Frame: 6 months ]
    Additional intravenous glucocorticoids, radiotherapy, orbital decompression, immunosuppressive treatments of any kind



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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  1. Informed consent
  2. A diagnosis of Graves' disease
  3. A moderately severe GO
  4. Active GO
  5. No corticosteroids or immunosuppressive treatment for GO in the last 3 months.
  6. No previous surgical treatment for GO
  7. No contraindication to GC
  8. Male and female patients of age: 18-75 years
  9. LDL-cholesterol levels of 115-189 mg/dl
  10. No more than one cardiovascular risk factor (diabetes, high blood pressure, smoking, familial history of acute cardiovascular events, obesity)
  11. Effective method of contraception
  12. No mental illness that prevent patients from comprehensive, written informed consent
  13. Compliant patient, regular follow-up possible

Exclusion Criteria:

  1. lack of informed consent
  2. Absence of Graves' hyperthyroidism (present or past)
  3. Inactive GO
  4. Optic neuropathy
  5. Corticosteroids or immunosuppressive treatment for GO in the last 3 months.
  6. Previous surgical treatment for GO
  7. Contraindications to GC
  8. Pregnancy, breast-feeding women
  9. Acute or chronic liver disease
  10. Hypersensitivity to atorvastatin or other statins, or hypersensitivity or intolerance to the medication excipients such as lactose.
  11. Medications interfering/interacting with statins (CYP3A4 inhibitors or inductors)
  12. Relevant Malignancy
  13. Corticosteroids or other immunosuppressive agents within last 3 months
  14. Recent (≤1 year) history of alcoholism or drug abuse
  15. Clinical ASCVD (AthroSclerotic CardioVascular Disease)
  16. LDL-cholesterol levels ≥190 mg/dl or presence of more than one associated cardiovascular risk factor (diabetes, high blood pressure, smoking, familial history of acute cardiovascular events, obesity)
  17. Severe familial hyperlipemia

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03110848


Contacts
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Contact: Michele Marinò, MD +39-348-0616959 michele.marino@med.unipi.it
Contact: Giulia Lanzolla, MD +39-340-7685085 giulia.lanzolla8@gmail.com

Sponsors and Collaborators
University of Pisa

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Responsible Party: Marinò Michele, Ricercatore (Assistant Professor), University of Pisa
ClinicalTrials.gov Identifier: NCT03110848     History of Changes
Other Study ID Numbers: STAGO
First Posted: April 12, 2017    Key Record Dates
Last Update Posted: June 7, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hypercholesterolemia
Graves Ophthalmopathy
Eye Diseases
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Eye Diseases, Hereditary
Graves Disease
Exophthalmos
Orbital Diseases
Genetic Diseases, Inborn
Goiter
Thyroid Diseases
Endocrine System Diseases
Hyperthyroidism
Autoimmune Diseases
Immune System Diseases
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Atorvastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Prednisolone hemisuccinate
Prednisolone phosphate
Glucocorticoids
Anticholesteremic Agents
Hypolipidemic Agents