Clinical trial NCT03110848: Effects of Atorvastatin in Graves' Orbitopathy (GO)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Thyroid Associated Ophthalmopathy
Hypercholesterolemia
Lead sponsor: University of Pisa
Sponsor class: OTHER
First posted: 2017-04-12
Enrollment: 88
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: Overall GO outcome determined using a composite evaluation
timeFrame: 6 months
Secondary outcomes:
measure: Overall GO outcome determined using a composite evaluation
timeFrame: 3 months
measure: Comparison of a disease specific quality of life questionnaire (GO-QoL)
timeFrame: 6 months
measure: Comparison of a disease specific quality of life questionnaire (GO-QoL)
timeFrame: 3 months
measure: GO relapse
timeFrame: 6 months
measure: Requirement for additional treatments
timeFrame: 3 months
measure: Requirement for additional treatments
timeFrame: 6 months
Other outcomes:
Locations:
city: Pisa
country: Italy
facility: Ospedale Cisanello-Endocrinology I and II
Study officials:
References:
citation: 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.