Thyroid Treatment Trial

Graves Ophthalmopathy Clinical Trial

Official title: Comparison of Efficacy and Safety of Intravenous Pulsed Methylprednisolone and Oral Methotrexate Versus Intravenous Pulsed Methylprednisolone and Oral Placebo in the Treatment of Active Moderate and Severe Thyroid Eye Disease - a Prospective, Randomized, Double-blind, Parallel, Controlled Multidisciplinary Clinical Trial and Imaging Study.

Status Completed

Clinical Trial Summary

This project will compare the efficacy and safety of 2 methods of disease modification in the treatment of active moderate and severe thyroid orbitopathy. A prospective, randomized, double-blind, parallel, controlled multidisciplinary clinical trial involving Singapore National Eye Centre, National University Hospital, Changi General Hospital, Tan Tock Seng Hospital and University of British Columbia Orbital Services, Singapore Eye Research Institute, Singapore General Hospital Endocrinology and Radiology Departments and Tan Tock Seng Hospital Rheumatology Department is planned. The SingHealth-SGH High Field MR Research Laboratory will be involved in the MR imaging of the trial patients.

Patients who satisfy the inclusion and exclusion criteria will be asked to participate in this trial. After informed consent (Appendix B) is obtained, each patient will be randomized into one of two treatment arms: 1) Intravenous high-dose pulsed methylprednisolone (1 gram infusion over 1 hour per day with a total of 3 doses over 3 days; 4 cycles at 6 weekly intervals) and oral placebo and 2) Intravenous high-dose pulsed methylprednisolone (same dose) plus oral methotrexate 7.5 mg per week for 2 weeks, increased to 10 mg per week for another 2 weeks then 12.5 mg per week for 5 months (total 6 months of methotrexate treatment). Depending on patient response, the dose can be further increased by 2.5mg per week every 4 weeks to a maximum of 20 mg per week. A strict management protocol will be observed for each recruited patient. Patients who develop adverse side effects or need for surgical intervention will receive appropriate treatment (i.e. treatment will deviate from the protocol but will continue to be monitored). Patients who refuse treatment will be observed clinically and with imaging as a natural control group until such time as intervention is accepted.

The patients will have a baseline assessment followed by regular visits to assess treatment response and adverse effects. Observations will include the use of an inflammatory index, motility measurements including quantitative ductions, exophthalmometry readings, palpebral aperture readings and indices of optic nerve function. With regards to the imaging, the patients will be assessed with an initial quantitative CT scan and 3-Tesla MRI scan prior to treatment. After treatment is started, patients will also undergo repeat MRI scan at 24 weeks and 72 weeks to assess quantitative changes with treatment using the Muscle Diameter Index (MDI) and Pixel Value Ratio (PVR) for the inferior rectus, superior rectus, the medial rectus, lateral rectus and orbital fat (Appendix E). Serum and urine will be obtained at the same time intervals as the MRI scan to assess levels of thyroid hormones, thyroid antibodies and urinary glycosaminoglycans (GAGs). Free T4, free T3 and TSH will be recorded to monitor control of hyperthyroidism. Thyroid antibodies measured will include thyroid stimulating immunoglobulin (TSI), thyrotropin-binding inhibition antibody (TB II), thyroid peroxidase antibodies and thyroglobulin antibody. Other tests including the full blood count, urea and electrolytes will be run prior to each dose of steroid treatment and during follow-up to monitor for adverse effects.

The results of the assessments will be analyzed for significant differences in treatment response between the 2 groups. The indices of interest will include the percentage of patients in each group who demonstrate a decrease in the inflammatory index of at least 2 points and the time taken for 50% of patients to show such a decrease. Other parameters that reflect the visual function and motility will be compared at different points in time after starting treatment to observe response and sustainability of response. From the serial MRI scans, quantitative analysis of orbital tissues will be done to identify changes with treatment. Antibody and GAG levels will be analyzed to detect any change with treatment. The types and frequency of adverse side effects in the 2 groups will also be assessed.

80 normal subjects will be recruited for MRI scan of the orbits and brain to obtain normative values for the MDI and PVR for the Asian population (Appendix E). This will include 20 subjects from each of 4 decades (21-30 years, 31-40 years, 41-50 years, 51-60 years).

The normative data will also be used to create a virtual orbital atlas. This aspect of the study will be performed in collaboration with the Labs for Information Technology (A-Star).

Clinical Trial Description

Since 1835 when Graves first described the eye changes in thyroid disease, considerable literature on investigating the basic disease process, the clinical behaviour, natural history and various medical and surgical treatments on thyroid orbitopathy has developed.

3.1 Pathogenesis 11, 12

HLA-DR histocompatibility loci which play a role in T-cell response have been associated with thyroid orbitopathy but no specific gene has been identified as yet.

It is believed that TSH receptors may be the autoantigen in Graves' hyperthyroidism, orbitopathy and pretibial myxoedema. Somehow, T-lymphocytes are activated and proceed to infiltrate orbital and other soft tissues. This sets off cytokine release which together with oxygen free radicals and fibrogenic growth factors leads to increased hydrophilic glycosaminoglycan (GAG) synthesis and pre-adipocyte transformation. The overall effect is an increase in orbital muscle and fat volume and inflammatory oedema which ultimately may result in muscle fibrosis and optic nerve compression.

3.2 Pathology

The histopathological features correlate with the immunogenetic theory in thyroid orbitopathy. The extraocular muscles are infiltrated by lymphocytes, macrophages, plasma cells and mast cells. Hydrophilic mucopolysaccharides are deposited and are seen separating the muscle bundles and fibres. In the later stages, fibrosis and muscle degeneration with fat replacement is noted.

3.3 Clinical Features

Based on literature review and the experience of the University of Columbia Orbital Clinic which saw over 2000 cases from 1976 to 2002.

1. Indices of disease activity (largely subjective)

• Acuity of onset and progression

• Acute (within a week) or subacute (3 months or under 3 months) or chronic onset (over 3 months)

• Slow or rapid development (progression)

• Subjective symptoms

• Spontaneous retrobulbar pain

• Pain on extraocular movement

• Soft tissue features

• Swelling, injection and chemosis noted by the patient

• Patient assessment of symptoms and signs - Same, better or worse

2. Indices of disease severity and extent (largely objective)

• Lid and conjunctival swelling

• Extraocular muscle function

• Proptosis

• Optic nerve function

• Imaging changes in orbital tissues The NOSPECS classification of thyroid orbitopathy 13,14 does not give a clear picture of disease activity and severity. It does not guide prognostication and management and is thus abandoned in favour of the above assessment which looks specifically at indices which allow one to judge whether the disease is active and how severe it is 1.

From such an assessment, a treatment algorithm can be formulated:

3.4 Current Treatment

Although the exact aetiology and pathophysiology of thyroid orbitopathy remains unclear, what is known about the disease suggests an autoimmune mechanism at work 1,2. The initial phase of the disease is marked by clinical inflammatory changes and is followed by quiescence during which cicatricial and persistent orbital volume changes are more pronounced. In this latter phase, surgery alone works to alleviate symptoms. To avoid these end-stage developments, the disease should be treated during the active stage.

A recent trend in the management of thyroid orbitopathy has been to treat active disease with intravenous pulsed methylprednisolone 1,3-8. This step away from oral steroids arose from a desire to avoid the many known complications of prolonged oral steroid use as well as perceived lower success rates with the use of oral steroids. Marcocci et al 9 published in August 2001 results of a prospective, single-blind, randomized study that compared the effectiveness and tolerability of intravenous or oral glucocorticoids in association with orbital radiotherapy in the treatment of severe Graves' ophthalmopathy. This and other studies found that both treatments were effective (60-85% showing improvement) with the intravenous route associated with a lower rate of side effects. 3,4,5,6,7,9 Another treatment was reported by Smith and Rosenbaum in the British Journal of Ophthalmology 10. They described the use of oral methotrexate in the management of non-infectious orbital inflammatory disease. In their study, there were 3 patients with recalcitrant thyroid orbitopathy who had previously been treated with oral prednisolone, irradiation and surgical decompression. Two were still on oral prednisolone when oral methotrexate was started. All 3 showed clinical benefit and the 2 who were also on steroids initially were eventually able to cease steroid use. The good response may well be due to the fact that methotrexate, with its T-cell inhibiting effect, succeeded in halting the disease process especially when used together with corticosteroid.

The current treatment for those with progressively worse moderate or severe disease is medical decompression with either corticosteroid with or without cyclosporin or immunosuppressive agents such as methotrexate, cyclophosphamide or azathioprine as adjuvant therapy. The use of these latter agents are not well studied. When the soft tissue inflammation and orbital congestion is relieved, surgical redress of mechanical problems follows.

The role of radiotherapy remains unclear 15. Gorman et al conducted a prospective, randomized double-blind, placebo-controlled study of orbital radiotherapy for Graves' ophthalmopathy which failed to demonstrate any beneficial therapeutic effect 16. However, the study was flawed by the broad patient inclusion criteria and initiation of radiotherapy at different stages of the disease. Other studies have reported effective use of radiotherapy in the treatment of Graves' ophthalmopathy. Mourits conducted a randomized placebo-controlled trial which showed that external beam irradiation produced improvement in ocular motility in patients with mild or moderate disease 17.

We propose that active moderate and severe thyroid orbitopathy can be treated more aggressively with intravenous pulsed methylprednisolone and oral methotrexate in order to better stabilise the disease process and prevent cicatricial or compressive events. The question that this study aims to answer is whether this is a better treatment option compared to the current treatment in terms of efficacy and safety. Assessing the antibody and urinary GAG levels will yield information on serum and urinary profiles during treatment. We previously reported associations between thyroid autoantibodies and ophthalmopathy 18. The study will also use a 3-Tesla MRI to obtain normative values (MDI and PVR) for the Asian population and to evaluate quantitative changes in thyroid-related orbitopathy. This will provide a framework to study other multimodality therapy, including T-cell suppression, specific immunoglobulins and antifibroblastic agents.

4. STUDY PURPOSE

The purpose of this study is to investigate the effectiveness and safety of combined intravenous steroid and oral methotrexate in the treatment of patients with active moderate or severe thyroid orbitopathy. A prospective, randomized, double-blind, parallel, controlled clinical trial designed with this aim will provide useful information to aid future multimodality trials. This concept is based on the trend in managing rheumatologic disorders where early aggressive targeted multimodality therapy has improved treatment. The results of this study will also complement a planned radiotherapy study at the University of British Columbia ;

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Eye Diseases
• Graves Ophthalmopathy

• NCT number: NCT00348413
• Study type: Interventional
• Source: Singapore National Eye Centre
• Status: Completed
• Phase: N/A
• Start date: June 2003
• Completion date: July 2008