Graves Ophthalmopathy, Graves Orbitopathy, Thyroid Eye Disease
Conditions
Keywords
graves orbitopapathy, thyroid eye disease, atorvastatin, statins, methylprednisolone, randomised controlled trial, orbital computed tomography, microRNA, graves ophthalmopathy
Brief summary
The trial tests the hypothesis that, in adults with active, moderate-to-severe Graves' orbitopathy, 24 weeks of oral atorvastatin 20 mg daily added to a standard 12-week course of intravenous methylprednisolone produces a greater reduction in extraocular muscle size than intravenous methylprednisolone alone, and that any such reduction is accompanied by lower expression of TSH receptor, IGF-1 receptor, PDGF receptor, PI3K/AKT and miR-155 transcripts, and higher expression of miR-146a. The prespecified direction for miR-146a follows its reported suppression in CD4+ T cells in active disease \[26\]. Reported directions of change are compartment-specific and not unanimous, so the transcript analyses are exploratory.
Interventions
DRUGAtorvastatin
Moderate-to-severe Graves' orbitopathy at a tertiary referral centre in Yogyakarta, Indonesia, will be allocated 1:1 to intravenous methylprednisolone (500 mg weekly for six weeks, then 250 mg weekly for six weeks) with oral atorvastatin 20 mg daily for 24 weeks.
Moderate-to-severe Graves' orbitopathy at a tertiary referral centre in Yogyakarta, Indonesia, will be allocated 1:1 to intravenous methylprednisolone (500 mg weekly for six weeks, then 250 mg weekly for six weeks)
Sponsors
Banu Aji Dibyasakti
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Age 18 to 75 years inclusive * Graves' orbitopathy graded moderate-to-severe by EUGOGO criteria * Active disease, clinical activity score ≥ 3 of 7 * Rehabilitative orbital decompression anticipated after completion of glucocorticoid therapy, on the usual clinical grounds * Able to attend weekly infusion visits and complete follow-up to week 48 * Written informed consent given * For women of childbearing potential, agreement to use effective contraception until week 24
Exclusion criteria
* Sight-threatening disease at screening: dysthyroid optic neuropathy or corneal breakdown * Any other autoimmune disease requiring systemic immunosuppresion * Known hypersensitivity to atorvastatin or to any statin * Current or recent (within 3 months) use of any lipid-lowering drug * Any contraindication to orbital decompression * Any independent indication for lipid-lowering therapy: established atherosclerotic cardiovascular disease, more than one cardiovascular risk factor (diabetes mellitus, hypertension, obesity), or LDL cholesterol ≥ 190 mg/dL * Systemic glucocorticoid or immunosuppressive treatment for orbitopathy within the preceding 3 months * Previous orbital irradiation or orbital surgery * Alanine or aspartate aminotransferase \> 3 × upper limit of normal, or creatine kinase \> 5 × upper limit of normal, at screening * Estimated glomerular filtration rate \< 30 mL/min/1.73 m² * Pregnancy at screening (confirmed by a negative test before randomisation) or breastfeeding * Concomitant treatment with a strong CYP3A4 inhibitor * Any condition that, in the opinion of the investigator, would prevent completion of the trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Individual rectus muscle diameters | At the first week,12th week, and 24th week from starting point of treatment | The primary outcome is measuring the rectus muscle diameters using Coronal CT, per muscle, both orbits |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite ocular response | At Week 24th | A participant is a responder if at least two of the five criteria below are met in the more affected eye, with no deterioration in any of them in either eye: 1. reduction in clinical activity score of 2 points or more; 2. reduction in proptosis of 2 mm or more, without an increase of 2 mm or more in the fellow eye; 3. reduction in vertical palpebral fissure height of 2 mm or more, with the same proviso for the fellow eye; 4. disappearance of diplopia, or improvement by at least one Gorman grade; 5. improvement in best-corrected visual acuity of 0.1 logMAR or more, this being the step on the logMAR chart closest to the 0.2-decimal criterion used in STAGO. |
| Clinical activity score | Baseline and every study visit to week 24 | 7-item EUGOGO scale, masked assessor Score : * Minimum score 0 and maximum score 7 at first meeting * Maximum score 10 at follow up meeting Higher score has worse outcome |
| Exophthalmos, clinical | Baseline and every study visit to week 24 | Measurement of clinic exophthalmos using Hertel exophthalmometer, fixed base setting, single masked assessor |
| Exophthalmos, radiological | Baseline, weeks 12, 24 | Exophthalmos measured from Interzygomatic line to posterior corneal surface, axial CT |
| Vertical palpebral fissure height | Baseline and every study visit to week 24 | Palpbral fissure height measured using millimetre ruler, primary position of gaze, masked assessor |
| Change in LDL cholesterol | Baseline, weeks 12, 24 | Using the Enzymatic colorimetric assay; used in the prespecified mediation analysis |
| Orbital fat volume | Baseline, weeks 12, 24 | Using Segmentation at -200 to -30 HU, ITK-SNAP v4.2.0 |
| Transcript levels in peripheral blood | Baseline, weeks 12, 24 | TSH-R, IGF-1R, PDGF-R, PI3K/AKT, miR-146a, miR-155; qRT-PCR, fold change relative to GAPDH for the messenger RNA targets and to U6 snRNA for the microRNA target |
| Transcript levels in orbital tissue | At decompression 24th week | TSH-R, IGF-1R, PDGF-R, PI3K/AKT, miR-146a, miR-155; qRT-PCR, fold change relative to GAPDH for the messenger RNA targets and to U6 snRNA for the microRNA targets; specimen taken at rehabilitative decompression |
Countries
Indonesia
Contacts
CONTACTBanu Aji Dibyasakti, MD
CONTACTNikolaus Erik Darmawan, MD
Outcome results
None listed