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

• ClinicalTrials.gov Identifier: NCT04776993
• Recruitment Status: Not yet recruiting
• First Posted: March 2, 2021
• Last Update Posted: February 2, 2022
• Sponsor: University of Pisa
• Information provided by (Responsible Party): Marinò Michele, University of Pisa

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Graves' Orbitopathy	Drug: Methimazole; Procedure: Radioiodine or thyroidectomy	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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)
• Estimated Study Start Date: April 1, 2022
• Estimated Primary Completion Date: October 30, 2022
• Estimated Study Completion Date: October 30, 2024

Arms and Interventions

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 Name: 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 Name: Thyroid ablation

Outcome Measures

Primary Outcome Measures :

1. Overall GO outcome [ Time Frame: 24 weeks ]

   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".

Secondary Outcome Measures :

1. Overall GO outcome [ Time Frame: 48 weeks ]

   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".

2. Overall GO outcome [ Time Frame: 72 weeks ]

   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".

3. Response of individual GO parameters: proptosis, CAS, eyelid width, diplopia, and visual acuity [ Time Frame: 24, 48 and 72 weeks ]

   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".

4. Quality of life questionnaire [ Time Frame: 24, 48 and 72 weeks ]
   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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Michele Marino; +39050997346; michele.marino@med.unipi.it

Contact: Giulia Lanzolla; +39050997346; giulia.lanzolla8@gmail.com

Locations

Italy

Endocrinology Unit II

Pisa, PI, Italy, 56124

Contact: Michele Marinò, MD +39050997346 michele.marino@med.unipi.it

Contact: Giulia Lanzolla, MD +39050997346 giulia.lanzolla8@gmail.com

Sponsors and Collaborators

University of Pisa

More Information

• Responsible Party: Marinò Michele, Associate Professor, University of Pisa
• ClinicalTrials.gov Identifier: NCT04776993
• Other Study ID Numbers: ABLAGO
• First Posted: March 2, 2021
• Last Update Posted: February 2, 2022
• Last Verified: February 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

Graves Ophthalmopathy; Hyperthyroidism; Thyroid Diseases; Endocrine System Diseases; Eye Diseases, Hereditary; Eye Diseases; Graves Disease; Exophthalmos; Orbital Diseases; Genetic Diseases, Inborn; Goiter; Autoimmune Diseases; Immune System Diseases; Methimazole; Antithyroid Agents; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs