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.
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 80
- 试验地点
- 2
- 主要终点
- Inflammatory index
研究概览
简要总结
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).
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double
入排标准
- 年龄范围
- 21 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Confirmed TED (as defined by Bartley and Gorman19)
- •Eyelid retraction (upper eyelid margin at or above the superior corneoscleral limbus in primary gaze without frontalis muscle contraction) in association with any one of the following:
- •Thyroid dysfunction or abnormal regulation (increased serum thyroxine or triiodothyronine level, decreased serum thyroid stimulating hormone level, absence of thyroid radioiodine uptake suppression after administration of triiodothyronine, or the presence of thyroid stimulating immunoglobulins in serum)
- •Exophthalmos (Hertel measurement of at least 20mm)
- •Extraocular muscle involvement (restrictive myopathy or objective evidence of enlarged muscles)
- •Optic nerve dysfunction (abnormal visual acuity, colour vision, pupillary reaction or perimetry not attributable to other causes)
- •Thyroid dysfunction or abnormal regulation in association with any one of the following:
- •Exophthalmos
- •Extraocular muscle involvement
- •Optic nerve dysfunction
- •Active disease
- •Inflammatory Index
- •Inflammatory Index
- •Soft tissue feature Rating Chemosis 0 Absent
- •Moderate (up to lid margin)
- •Severe (over lid margin; persists on closing eye)
- •Conjunctival injection 0 Absent 1 Present
- •Lid injection 0 Absent
- •Lid edema 0 Absent
- •Severe (festoons, overhang)
- •Pain at rest (clearly defined as retrobulbar aching) 0 Absent 1 Present
- •Pain on movement 0 Absent
- •Total possible 8
- •Active disease is defined as an inflammatory index of at least 3 together with acute or subacute onset (3 months and under) and/or evidence of progression (from history or clinical observation).
- •(3) Moderate or severe disease
- •Primary Criteria
- •Mild Moderate Severe Inflammatory Index <3 3-5 >5
- •Motility <1/3 1/3 to 2/3 >2/3 (involving any one muscle) limitation limitation Limitation
- •Elevation, depression, adduction and abduction of the individual eyes will be measured with a modified Aimarck perimeter with input from both patient and the orthoptist who performs the test
- •Secondary Criteria 21,22,23,24
- •Mild Moderate Severe Exophthalmos (mm) <21 21-24 25 or more
- •Best corrected vision (Logmar) - - 0.6 or worse
- •CT criterion (Muscle Diameter Index) 21-24 25-30 31 and above
- •These criteria are not considered absolutes and emphasize measurable indices based on previous studies.
- •The presence of at least 1 primary criterion and at least 1 secondary criterion places the patient in the more advanced disease group (in the situation where 1 primary criterion is mild and the other severe, the presence of 1 severe secondary criterion will yield a severe grade whereas absence of this criterion will result in a mild grade) eg 1) a patient with an inflammatory index of 6 and moderate limitation of extraocular motility, 21mm proptosis, 0.3 vision and MDI of 26 has moderate disease as the secondary criteria for severe disease was not present eg 2) a patient with an inflammatory index of 5 and mild limitation of extraocular motility, 21mm proptosis, 0.3 vision and MDI of 30 has moderate disease as 1 primary and 2 secondary criteria for moderate disease were present eg 3) a patient with inflammatory index of 6 and mild limitation of extraocular motility, 20mm proptosis, 0.3 vision and MDI of 21 has mild disease as the secondary criterion for severe disease was absent and the other primary parameter (motility) was graded mild.
- •(4) Age between 21 - 60
- •(5) Written informed consent is obtained
排除标准
- •Previous treatment for TED
- •Oral steroids (e.g. immunosuppressive dose) for last 3 months, radiotherapy
- •Intravenous pulsed steroid or methrotrexate therapy
- •Medically unfit to receive I/V high-dose pulsed methylprednisolone or methotrexate
- •History of cardiac arrthymias, recent acute myocardial infarction
- •History of seizure
- •History of acute bleeding peptic ulcer
- •History of pulmonary tuberculosis, Hepatitis B carrier, Hepatitis C positivity, HIV
- •Uncontrolled diabetes or hypertension (to be eligible for the trial, random blood glucose must be < 11.1 mmol/L and blood pressure must be 140/90 or lower#. If above these limits, patients can be treated and reviewed at 2 weeks for enrolment when criteria are met - provided the patient does not have optic neuropathy)
- •Hepatic dysfunction (Alb, AST, ALT and Alkaline phosphates levels must be within normal range for eligibility)
- •Renal impairment (Urea and Creatinine levels must be within normal range)
- •Abnormal blood count (outside normal range)
- •Fertile females considering becoming pregnant during the course of the study and those not willing to take precautions to avoid pregnancy
- •Both female and male planning to start a family during the trial period or within 6 months of stopping the drugs
- •History of seizure
- •History of mental / psychiatric disorder
- •Patients with clinical features of optic nerve disc pallor at primary presentation will be excluded
结局指标
主要结局
Inflammatory index
次要结局
- Proptosis
- Motility