A Conservative vs an Ablative Approach for Treatment of Hyperthyroidism in Patients With Graves' Orbitopathy

NCT04776993 | Recruiting Phase 3

• 1 other identifier: ABLAGO
• Study Type: interventional
• Target: 52
• Locations: 1 country
• Sites: 1

Brief Summary

Graves' disease (GD) is the most frequent cause of hyperthyroidism in iodine sufficient countries and Graves' orbitopathy (GO) is its most common extrathyroidal manifestation. Restoration and maintenance of euthyroidism are imperative in Graves' disease patients with GO. The main treatment options for Graves' hyperthyroidism are antithyroid drugs, radioactive iodine (RAI), and surgery. Whether one or the other therapy for Graves' hyperthyroidism offers the best protection against GO is not established. The study is aimed at comparing the effects of a conservative approach (antithyroid drugs, ATDs, experimental arm) vs an ablative approach (radioiodine or total thyroidectomy) of thyroid treatment on the overall outcome of GO in patients with GD and moderate-to-severe and active GO treated with intravenous glucocorticoids.

Conditions

Graves' Orbitopathy

Outcome Measures

Primary Outcomes (1)

• Overall GO outcome

  Improvement is defined as change in two of the following outcome measures in at least one eye, without deterioration in any of the same measures in both eyes (compared to baseline): * Improvement in CAS by at least 2 points * Improvement in exophthalmos by at least 2 mm (Hertel exophthalmometer) * Improvement in lid aperture by at least 2 mm * Improvement in diplopia (disappearance or change in the degree) * Improvement of visual acuity by at least 0.2/1 Patients meeting the improvement criteria will be considered as "responders". All other patients will be considered as "non-responders".

  24 weeks

Secondary Outcomes (4)

• Overall GO outcome

  48 weeks

• Overall GO outcome

  72 weeks

• Response of individual GO parameters: proptosis, CAS, eyelid width, diplopia, and visual acuity

  24, 48 and 72 weeks

• Quality of life questionnaire

  24, 48 and 72 weeks

Study Arms (2)

Methimazole

EXPERIMENTAL

Antithyroid drugs (at individualized dosage) for 72 weeks and a cumulative dose of 4.5 g of methylprednisolone divided into 12 weekly infusions

Drug: Methimazole

Thyroid ablation

ACTIVE COMPARATOR

Radioiodine therapy or total thyroidectomy (according to ultrasound thyroid volume) and a cumulative dose of 4.5 g of methylprednisolone divided into 12 weekly infusions

Procedure: Radioiodine or thyroidectomy

Interventions

Methimazole DRUG

Methimazole for 72 weeks

Also known as: MMI

Methimazole

Radioiodine or thyroidectomy PROCEDURE

Treatment with radioiodine or with thyroidectomy

Also known as: Thyroid ablation

Thyroid ablation

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.
• Duration of Graves' disease shorter than 18 months
• A moderate-to-severe GO, defined as the presence of at least one of the following criteria in the most affected eye: an exophthalmos ≥2 mm compared with normal values for sex and race; presence of inconstant to constant diplopia; a lid retraction ≥2 mm
• Active GO: CAS ≥ 3 out of 7 points in the most affected eye. Taking into account severity (moderate-to-severe) and activity (CAS ≥ 3/7) of GO, patients are eligible for methylprednisolone treatment according to clinical practice.
• Duration of GO shorter than 18 months
• Male and female patients of age 18-75 years
• Compliant patient, regular follow-up possible

You may not qualify if:

• Optic neuropathy
• Previous therapy for Graves' disease with radioiodine or thyroidectomy
• Corticosteroids or other immunosuppressive treatment for GO or other reasons in the last 3 months.
• Previous surgical treatment and/or radiotherapy for GO
• 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)
• Acute or chronic liver disease
• Contraindications to ATD: hypersensitivity to the active substance or to any of the excipients; breastfeeding
• 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")
• Contraindications of any kind to perform thyroidectomy
• Mental illness that prevent patients from comprehensive, written informed consent

Sponsors & Collaborators

• University of Pisa: lead

Study Sites (1)

Endocrinology Unit II

Pisa, PI, 56124, Italy

RECRUITING

MeSH Terms

Conditions

Graves Ophthalmopathy

Interventions

Methimazole; Iodine-131; Thyroidectomy

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)

Sulfhydryl Compounds; Sulfur Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Endocrine Surgical Procedures; Surgical Procedures, Operative

Central Study Contacts

Michele Marino

CONTACT

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

Giulia Lanzolla

CONTACT

+39050997346; giulia.lanzolla8@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: February 25, 2021
• First Posted: March 2, 2021
• Study Start: March 2, 2023
• Primary Completion: September 1, 2024
• Study Completion: March 1, 2026
• Last Updated: March 17, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)