Effects of Atorvastatin in Graves' Orbitopathy (GO)

NCT03110848 | Completed Phase 2

• 1 other identifier: STAGO
• Study Type: interventional
• Target: 88
• Locations: 1 country
• Sites: 1

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.

Conditions

Thyroid Associated Ophthalmopathy; Hypercholesterolemia

Outcome Measures

Primary Outcomes (1)

• Overall GO outcome determined using a composite evaluation

  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)

  6 months

Secondary Outcomes (6)

• Overall GO outcome determined using a composite evaluation

  3 months

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

  6 months

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

  3 months

• GO relapse

  6 months

• Requirement for additional treatments

  3 months

Study Arms (2)

Statins

EXPERIMENTAL

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; Drug: Methylprednisolone

No statins

ACTIVE COMPARATOR

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

Interventions

Atorvastatin DRUG

Atorvastatin 20 mg daily

Also known as: Statins

Statins

Methylprednisolone DRUG

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.

Also known as: Intravenous glucocorticoids

No statins; Statins

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• lack of informed consent
• Absence of Graves' hyperthyroidism (present or past)
• Inactive GO
• Optic neuropathy
• Corticosteroids or immunosuppressive treatment for GO in the last 3 months.
• Previous surgical treatment for GO
• Contraindications to GC
• Pregnancy, breast-feeding women
• Acute or chronic liver disease
• Hypersensitivity to atorvastatin or other statins, or hypersensitivity or intolerance to the medication excipients such as lactose.
• Medications interfering/interacting with statins (CYP3A4 inhibitors or inductors)
• Relevant Malignancy
• Corticosteroids or other immunosuppressive agents within last 3 months
• Recent (≤1 year) history of alcoholism or drug abuse
• Clinical ASCVD (AthroSclerotic CardioVascular Disease)

Sponsors & Collaborators

• University of Pisa: lead

Study Sites (1)

Ospedale Cisanello-Endocrinology I and II

Pisa, 56124, Italy

Location

Related Publications (1)

• Lanzolla G, Sabini E, Leo M, Menconi F, Rocchi R, Sframeli A, Piaggi P, Nardi M, Marcocci C, Marino M. Statins for Graves' orbitopathy (STAGO): a phase 2, open-label, adaptive, single centre, randomised clinical trial. Lancet Diabetes Endocrinol. 2021 Nov;9(11):733-742. doi: 10.1016/S2213-8587(21)00238-2. Epub 2021 Sep 27.

  PMID: 34592164 DERIVED

MeSH Terms

Conditions

Graves Ophthalmopathy; Hypercholesterolemia

Interventions

Atorvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Methylprednisolone

Condition Hierarchy (Ancestors)

Eye Diseases, Hereditary; Eye Diseases; Graves Disease; Exophthalmos; Orbital Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Goiter; Thyroid Diseases; Endocrine System Diseases; Hyperthyroidism; Autoimmune Diseases; Immune System Diseases; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Enzyme Inhibitors; Lipid Regulating Agents; Therapeutic Uses; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: INVESTIGATOR
• Masking Details: Ophthalmologist blinded to treatment
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Ricercatore (Assistant Professor)

Study Record Dates

• First Submitted: March 23, 2017
• First Posted: April 12, 2017
• Study Start: June 1, 2020
• Primary Completion: April 30, 2021
• Study Completion: April 30, 2021
• Last Updated: August 13, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)