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

A Phase III, Randomized, Controlled, Open Label, no Profit, Single-center Intervention Study to Compare the Effect of a Conservative (Antithyroid Drugs) and an Ablative Approach (Radioiodine or Total Thyroidectomy) for the Treatment of Hyperthyroidism in Patients With Graves' Disease and Moderate-to-severe and Active Graves' Orbitopathy (GO) Treated With Intravenous Glucocorticoids (ABLAGO Study)

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.

Study Overview

• Status: Recruiting
• Conditions: Graves' Orbitopathy
• Intervention / Treatment: Drug: Methimazole; Procedure: Radioiodine or thyroidectomy

• Study Type: Interventional
• Enrollment (Anticipated): 52
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Michele Marino; Phone Number: +39050997346; Email: michele.marino@med.unipi.it
• Study Contact Backup: Name: Giulia Lanzolla; Phone Number: +39050997346; Email: giulia.lanzolla8@gmail.com

Study Locations

• Italy
  • PI
    • Pisa, PI, Italy, 56124
      • Recruiting
      • Endocrinology Unit II
      • Contact: Michele Marinò, MD; Phone Number: +39050997346; Email: michele.marino@med.unipi.it
      • Contact: Giulia Lanzolla, MD; Phone Number: +39050997346; Email: giulia.lanzolla8@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients willing and capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
2. 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.
3. Duration of Graves' disease shorter than 18 months
4. 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
5. 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.
6. Duration of GO shorter than 18 months
7. Male and female patients of age 18-75 years
8. Compliant patient, regular follow-up possible

Exclusion Criteria:

1. Optic neuropathy
2. Previous therapy for Graves' disease with radioiodine or thyroidectomy
3. Corticosteroids or other immunosuppressive treatment for GO or other reasons in the last 3 months.
4. Previous surgical treatment and/or radiotherapy for GO
5. 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.
6. Use of medications interfering with GC or increasing the risk of GC-related adverse events (see prohibited therapies)
7. Acute or chronic liver disease
8. Contraindications to ATD: hypersensitivity to the active substance or to any of the excipients; breastfeeding
9. 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")
10. Contraindications of any kind to perform thyroidectomy
11. Mental illness that prevent patients from comprehensive, written informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Methimazole; 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; Methimazole for 72 weeks; Other Names: MMI
Active Comparator: Thyroid ablation; 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; Treatment with radioiodine or with thyroidectomy; Other Names: Thyroid ablation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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".	48 weeks
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".	72 weeks
Response of individual GO parameters: proptosis, CAS, eyelid width, diplopia, and visual acuity	Improvement is defined as change in each of the following outcome measures in at least one eye, without deterioration 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, 48 and 72 weeks
Quality of life questionnaire	Comparison of a disease specific quality of life questionnaire (GO-QoL) at 24, 48 and 72 weeks. Positive response: an improvement in the questionnaire by at least 6/48 points. The GO-QoL contains 8 questions on visual functioning and 8 questions on appearance. The minimal clinically important difference in scores is ≥ 10 points for invasive therapies, but a change of 6 is already perceived by patients as beneficial and is associated with an important change in daily functioning. The GO-QoL is well validated, widely used, and available in eight languages. The GO-QoL is recommended as an independent outcome measure in randomized clinical trials24.	24, 48 and 72 weeks

Collaborators and Investigators

• Sponsor: University of Pisa

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2023
• Primary Completion (Anticipated): September 1, 2024
• Study Completion (Anticipated): March 1, 2026

Study Registration Dates

• First Submitted: February 25, 2021
• First Submitted That Met QC Criteria: February 25, 2021
• First Posted (Actual): March 2, 2021

Study Record Updates

• Last Update Posted (Actual): March 17, 2023
• Last Update Submitted That Met QC Criteria: March 14, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Eye Diseases; Endocrine System Diseases; Genetic Diseases, Inborn; Thyroid Diseases; Eye Diseases, Hereditary; Graves Disease; Exophthalmos; Orbital Diseases; Goiter; Graves Ophthalmopathy; Hyperthyroidism; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Antithyroid Agents; Methimazole
• Other Study ID Numbers: ABLAGO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No