Hydroxychloroquine in Mild Graves' Orbitopathy

Study Overview
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Brief Summary
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This study is aimed to investigate the effect of hydroxychloroquine in patients with mild Graves' orbitopathy (GO).

Detailed Description
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Graves' orbitopathy (GO) is one of the common manifestations of Graves' disease (GD), which results in proptosis, eyelid retraction, soft tissue swelling, diplopia or even visual acuity impairment. In addition, mental health and quality of life are often affected. In current guidelines, limited treatment options are suggested for patients with mild GO. Recently, cell study revealed that there are multiple effects of hydroxychloroquine (HCQ) on orbital fibroblasts in patients with mild GO, including suppression of cell proliferation, adipogenesis and production of hyaluronic acid, which poses a great potential in the treatment of mild GO clinically. This randomized controlled trial is aimed to investigate the effects of HCQ in patients with mild GO on the effects of ophthalmic outcomes, quality of life, orbital volumetry on orbital computed tomography, serum inflammatory and fibrosis markers.

Official Title
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A Randomized Controlled Trial on the Effect of Hydroxychloroquine in Mild Graves' Orbitopathy

Conditions
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Graves Ophthalmopathy

Intervention / Treatment
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* Drug: Hydroxychloroquine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Mild GO according European Group on Graves' orbitopathy (EUGOGO) guidelines diagnosed by endocrinologist and ophthalmologist. No previous treatment of GO except for eyedrops Euthyroidism (normalized free T4 and TSH) for at least 2 months. If radioactive iodine is used for hyperthyroidism, euthyroidism needs to be achieved for at least 6 months. Exclusion Criteria: Moderate-to-sever or sight-threatening GO according to EUGOGO guidelines diagnosed by endocrinologist and ophthalmologist. Pregnancy Drug or alcohol abuse Unable to comply with the study protocol Unable to obtain informed consent Use of hydroxychloroquine or systemic steroid within 3 months prior to enrollment History of side effects of hydroxychloroquine History of retinopathy Renal dysfunction (estimated glomerular filtration rate (eGFR) < 60ml/min) Hepatic dysfunction (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 x upper limit) Anemia (hemoglobin (Hb) < 10g/dl) Neutropenia (absolute neutrophil count < 100/uL) Thrombocytopenia (platelet (PLT) < 150000/uL) Glucose-6-phosphate dehydrogenase (G6PD) deficiency Porphyria cutaneous tarda Allergy to 4-aminoquinoline

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydroxychloroquine<br>Hydroxychloroquine 200mg twice daily for 6 months. | Drug: Hydroxychloroquine<br>* Compare the effects of hydroxychloroquine 200mg twice daily for 6 months with those without treatment.<br>* Other names: Plaquenil;|
| No Intervention: Control<br>Observation and active surveillance. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change of ophthalmic outcome | The ophthalmic outcome is a composite outcome which includes three components: eyelid aperture, soft tissue involvement and exophthalmos. The outcome is defined as improvement if any of the three components improves without deterioration of any other components. The outcome of deterioration is defined if upgrading of soft tissue involvement or evidence of worsening sight or optic nerve compression. The outcome of stable is defined if the ophthalmic outcome does not fit the definition of improvement or deterioration. | at 24 weeks and 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change of quality of life (GO-QoL) | The outcome is grading as improvement, stable and deterioration. Improvement is defined if there are more than 6 points increase in any of the category in GO-QoL. Deterioration is defined if there are more than 6 points decrease in any of the category in GO-QoL. Stable is defined if none of above criteria is achieved. | at 24 weeks and 48 weeks | 
| The change of muscle volume (cm^3) on computed tomography | Change of muscle volume on noncontrast orbital CT | at 24 weeks and 48 weeks | 
| The change of fat volume (cm^3) on computed tomography | Change of fat volume on noncontrast orbital CT | at 24 weeks and 48 weeks | 
| The change of orbital volume (cm^3) on computed tomography | Change of orbital volume on noncontrast orbital CT | at 24 weeks and 48 weeks | 
| The change of muscle density on computed tomography | The density of muscle is measured and recorded in Hounsfield units. | at 24 weeks and 48 weeks | 
| The change of fat density on computed tomography | The density of fat is measured and recorded in Hounsfield units. | at 24 weeks and 48 weeks | 
| The change of diplopia score | The Gorman diplopia score includes four categories: no diplopia(absent), diplopia when the patient is tired or awakening (intermittent), diplopia at extremes of gaze (inconstant), and continuous diplopia in the primary or reading position (constant). | at 24 weeks and 48 weeks | 
| The change of clinical activity score (CAS) | Clinical activity score (CAS) is a 7-point scale using to evaluate the activity of GO in each eye. It includes 7 items to be scored respectively in each eye with minimum 0 point and maximum 7 points. More points indicate that GO in the eye is more active. The 7 items are listed as below: Spontaneous orbital pain Gaze evoked orbital pain Eyelid swelling that is considered to be due to active GO Eyelid erythema Conjunctival redness that is considered to be due to active GO Chemosis Inflammation of caruncle OR plica | at 24 weeks and 48 weeks | 
| The change of visual acuity | Evaluation of visual acuity will be done by the same ophthalmologist | at 24 weeks and 48 weeks | 
| The change of antithyroid peroxidase antibody (anti-TPO) (IU/mL) | Change of thyroid autoantibodies | at 24 weeks and 48 weeks | 
| The change of thyroglobulin antibody (TA) (IU/mL) | Change of thyroid autoantibodies | at 24 weeks and 48 weeks | 
| The change of thyrotropin-binding inhibiting immunoglobulin (TBII) (%). | Change of thyroid autoantibodies | at 24 weeks and 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Graves' ophthalmopathy, Graves' disease, Hydroxychloroquine, Orbital volumetry, GO-QoL questionnaire