Clinical Trial: Thyroid Treatment Trial
Study Status: Completed
Recruit Status: Completed
Study Type: Interventional
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 S
Brief 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.
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.
- Same as current
- Motility
- Proptosis
Current Secondary Outcome:
Original Secondary Outcome: Same as current
Information By: Singapore National Eye Centre
Dates:
Date Received: July 3, 2006
Date Started: June 2003
Date Completion:
Last Updated: May 11, 2010
Last Verified: May 2010
