A Randomized Clinical Trial to Evaluate the Effects of Atorvastatin on Graves' Orbitopathy (GO): the STAGO-2 Study

NCT05049603 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: STAGO-2
• Study Type: interventional
• Target: 102
• Locations: 1 country
• Sites: 1

Brief Summary

Graves' orbitopathy (GO) is the most common extra-thyroidal manifestation of Graves' disease (GD). Based on its clinical signs and symptoms, GO is graded as mild, moderate-to-severe, or severe, and active or inactive, the latter feature being established on a 5/7-scale score named Clinical Activity Score (CAS). The European Group on Graves Orbitopathy (EUGOGO) has recently formulated and published up-to-date guidelines for the management of GO, according to which high dose intravenous (iv) glucocorticoids (GC) (ivGC) is the first line treatment for moderate-to-severe and active GO. A protective effect of atorvastatin on the development of GO in patients with GD has been reported, based on which we recently conducted a phase II, randomized, open label clinical trial and found that atorvastatin improves the response of GO to ivGCs in hypercholesterolemic patients. The effect was unrelated to cholesterol levels, suggesting that it may be the consequence of a direct action of atorvastatin. To investigate this issue further and to introduce atorvastatin in the clinical practice, we designed the present Phase III, double-blinded, multicenter, randomized, adaptive, superiority, no profit, clinical trial to evaluate the effects of atorvastatin on Graves' Orbitopathy (GO) in patients with moderate-to-severe and active GO subjected to intravenous glucocorticoid therapy, regardless of cholesterol levels.

Conditions

Graves' Orbitopathy

Outcome Measures

Primary Outcomes (1)

• Outcome of GO

  Comparison of overall GO outcome determined using a composite evaluation (% of responders). Response is defined as change in two outcome measures in at least one eye, without deterioration in any of the same measures in both eyes (compared to baseline): Patients meeting the improvement criteria will be considered as "responders". All other patients will be considered as "non-responders".

  24 weeks

Secondary Outcomes (7)

• Outcome of GO

  12 weeks

• Outcome of GO

  48 weeks

• Quality of life (comparison between the two groups)

  12 weeks

• Quality of life (comparison between the two groups)

  24 weeks

• Quality of life (comparison between the two groups)

  48 weeks

Study Arms (2)

Atorvastatin

EXPERIMENTAL

Atorvastatin 20 mg/day (the experimental treatment), one tablet/day, given approximately at 10 pm, after dinner and before going to bed, for 24 weeks, associated with intravenous methylprednisolone pulse therapy (the standard treatment), given over a period of 12 weeks

Drug: Atorvastatin 20mg

Placebo

PLACEBO COMPARATOR

Intravenous methylprednisolone pulse therapy (the standard treatment), given over a period of 12 weeks, and placebo (one tablet/day, given approximately at 10 pm, after dinner and before going to bed) for 24 weeks

Other: Placebo

Interventions

Atorvastatin 20mg DRUG

One tablet/day, given approximately at 10 pm, after dinner and before going to bed, for 24 weeks

Also known as: Study Group

Atorvastatin

Placebo OTHER

One tablet/day, given approximately at 10 pm, after dinner and before going to bed, for 24 weeks

Also known as: Placebo group

Placebo

Eligibility Criteria

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

You may qualify if:

• Patients willing and capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
• A diagnosis of Graves' disease based on the presence of hyperthyroidism associated with detectable anti-thyrotropic hormone (TSH) receptor autoantibodies (TRAb). Patients must be euthyroid under control on stable medical regimen and every effort will be made to maintain the euthyroid status for the entire duration of the clinical trial
• A moderate-to-severe GO, defined as the presence of at least one of the following criteria: an exophthalmos ≥2 mm compared with normal values for sex and race; presence of inconstant to constant diplopia; a lid retraction ≥2 mm, lasting since no longer than 9 months
• Active GO: CAS (4) ≥ 3 out of 5 points in the most affected eye
• Male and female patients of age: 18-75 years
• AST, ALT and CPK levels ≤ 3 times the upper value of normal range
• Women of childbearing potential (WOCBP, namely not in menopause or in menopause since less than two years; in all other instances women will be considered as non-WOCBP) and men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year (as indicated in Appendix) for at least 6 and 7,5 months, respectively, after the last dose of the investigational drug (see also 2014\_09\_HMA\_CTFG\_Contraception.pdf, namely the "2014 CTFG Reccommendtions related to contraception and pregnancy testing in clinical trials").
• Compliant patient, regular follow-up possible

You may not qualify if:

• Optic neuropathy
• Corticosteroids or immunosuppressive treatment for GO in the last 3 months. Use of selenium in the last 3 months or during the clinical trial
• Previous surgical or radiant (orbital irradiation) treatment for GO
• Radioiodine treatment for hyperthyroidism over the last 3 months, as it can affect GO (4)
• Statin treatment in the last 3 months
• Contraindications to GC: hypersensitivity to the active substance or to any of the excipients; uncontrolled hypertension, uncontrolled diabetes; history of peptic ulcer; urinary infections, glaucoma, systemic fungal infections, systemic infections unless appropriate therapy is employed, idiopathic thrombocytopenic purpura, cerebral edema associated with malaria. Use of medications interfering with GC or increasing the risk of GC-related adverse events (see prohibited therapies)
• Pregnant or lactating females as determined by positive serum or urine HCG test at baseline
• Acute or chronic liver disease
• All factors that could increase the risk of rhabdomyolysis, in particular medications that could increase this risk (see prohibited therapies)
• Contraindications to statins, namely: hypersensitivity to atorvastatin or other statins, or hypersensitivity or intolerance to the medication excipients such as lactose; current or past liver diseases; alterations of liver tests.
• Medications interfering/interacting with statins (see prohibited therapies)
• Relevant Malignancy
• Recent (≤1 year) history of alcoholism or drug abuse
• Mental illness that prevent patients from comprehensive, written informed consent

Sponsors & Collaborators

• University of Pisa: lead
• Università degli Studi dell'Insubria: collaborator
• University of Catania: collaborator
• University of Messina: collaborator

Study Sites (1)

Ospedale Cisanello-Endocrinology II

Pisa, 56124, Italy

Location

MeSH Terms

Conditions

Graves Ophthalmopathy

Interventions

Atorvastatin

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

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids

Central Study Contacts

Michele Marinò, MD

CONTACT

+39050997346; michele.marino@med.unipi.it

Giulia Lanzolla, MD

CONTACT

+393407685085; giulia.lanzolla8@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The study will be double-blinded. Investigational Pharmacy will prepare identical bottles containing the medications. Each bottle will be marked with a code, to be assigned to a patient. Once a patient is screened and eligible, upon request from Centers, Investigational Pharmacy will send sets of 2 bottles per patient (one containing atorvastatin and one containing placebo). Following randomization, the Investigational Pharmacy will communicate to the Center the code of the bottle to be used. On-site principal investigators will be entitled to identify a patient's intervention only in the case of an emergency. Data from patients collected in an online, password-protected, central database, will be handled by the statistician, who will perform the final analyses. The statistician will be informed the Investigational Pharmacy to which randomization group patients were assigned to, in order to perform the analysis
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Model Details: Standard therapy (intravenous glucocorticoids) plus atorvastatin vs standard therapy plus placebo

Study Record Dates

• First Submitted: September 2, 2021
• First Posted: September 20, 2021
• Study Start: January 1, 2024
• Primary Completion: December 31, 2025
• Study Completion (Estimated): December 31, 2026
• Last Updated: March 15, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)