Thyroid Treatment Trial

NCT00348413 | Completed

• 1 other identifier: R272/16/2002
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

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. 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).

Conditions

Graves Ophthalmopathy

Keywords

Graves ophthalmopathy/therapy; Randomized controlled trial; Methylprednisolone; Methotrexate

Outcome Measures

Primary Outcomes (1)

• Inflammatory index

Secondary Outcomes (2)

• Motility

• Proptosis

Interventions

Intravenous Methylprednisolone + Oral Methotrexate vs Intravenous Methylprednisolone + Placebo DRUG

Eligibility Criteria

• Age: 21 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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)

You may not qualify if:

• 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)
• Others
• 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

Sponsors & Collaborators

• Singapore National Eye Centre: lead
• International Stem Cell Forum: collaborator

Study Sites (1)

Singapore National Centre

Singapore, 168751, Singapore

Location

Related Publications (19)

• Warwar RE. New insights into pathogenesis and potential therapeutic options for Graves orbitopathy. Curr Opin Ophthalmol. 1999 Oct;10(5):358-61. doi: 10.1097/00055735-199910000-00014.

  PMID: 10621552 BACKGROUND

• Nagayama Y, Izumi M, Kiriyama T, Yokoyama N, Morita S, Kakezono F, Ohtakara S, Morimoto I, Okamoto S, Nagataki S. Treatment of Graves' ophthalmopathy with high-dose intravenous methylprednisolone pulse therapy. Acta Endocrinol (Copenh). 1987 Dec;116(4):513-8. doi: 10.1530/acta.0.1160513.

  PMID: 3321820 BACKGROUND

• Kendall-Taylor P, Crombie AL, Stephenson AM, Hardwick M, Hall K. Intravenous methylprednisolone in the treatment of Graves' ophthalmopathy. BMJ. 1988 Dec 17;297(6663):1574-8. doi: 10.1136/bmj.297.6663.1574.

  PMID: 2906260 BACKGROUND

• Guy JR, Fagien S, Donovan JP, Rubin ML. Methylprednisolone pulse therapy in severe dysthyroid optic neuropathy. Ophthalmology. 1989 Jul;96(7):1048-52; discussion 1052-3. doi: 10.1016/s0161-6420(89)32784-9.

  PMID: 2771352 BACKGROUND

• Hiromatsu Y, Tanaka K, Sato M, Kuroki T, Nonaka K, Kojima K, Nishimura H, Nishida H, Kaise N. Intravenous methylprednisolone pulse therapy for Graves' ophthalmopathy. Endocr J. 1993 Feb;40(1):63-72. doi: 10.1507/endocrj.40.63.

  PMID: 7951498 BACKGROUND

• Koshiyama H, Koh T, Fujiwara K, Hayakawa K, Shimbo S, Misaki T. Therapy of Graves' ophthalmopathy with intravenous high-dose steroid followed by orbital irradiation. Thyroid. 1994 Winter;4(4):409-13. doi: 10.1089/thy.1994.4.409.

  PMID: 7711503 BACKGROUND

• Tagami T, Tanaka K, Sugawa H, Nakamura H, Miyoshi Y, Mori T, Nakao K. High-dose intravenous steroid pulse therapy in thyroid-associated ophthalmopathy. Endocr J. 1996 Dec;43(6):689-99. doi: 10.1507/endocrj.43.689.

  PMID: 9075609 BACKGROUND

• Marcocci C, Bartalena L, Tanda ML, Manetti L, Dell'Unto E, Rocchi R, Barbesino G, Mazzi B, Bartolomei MP, Lepri P, Cartei F, Nardi M, Pinchera A. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves' ophthalmopathy: results of a prospective, single-blind, randomized study. J Clin Endocrinol Metab. 2001 Aug;86(8):3562-7. doi: 10.1210/jcem.86.8.7737.

  PMID: 11502779 BACKGROUND

• Smith JR, Rosenbaum JT. A role for methotrexate in the management of non-infectious orbital inflammatory disease. Br J Ophthalmol. 2001 Oct;85(10):1220-4. doi: 10.1136/bjo.85.10.1220.

  PMID: 11567968 BACKGROUND

• Crisp M, Starkey KJ, Lane C, Ham J, Ludgate M. Adipogenesis in thyroid eye disease. Invest Ophthalmol Vis Sci. 2000 Oct;41(11):3249-55.

  PMID: 11006210 BACKGROUND

• Werner SC. Modification of the classification of the eye changes of Graves' disease. Am J Ophthalmol. 1977 May;83(5):725-7. doi: 10.1016/0002-9394(77)90140-4.

  PMID: 577380 BACKGROUND

• Van Dyk HJ. Orbital Graves' disease. A modification of the "NO SPECS" classification. Ophthalmology. 1981 Jun;88(6):479-83.

  PMID: 6894971 BACKGROUND

• Gorman CA, Garrity JA, Fatourechi V, Bahn RS, Petersen IA, Stafford SL, Earle JD, Forbes GS, Kline RW, Bergstralh EJ, Offord KP, Rademacher DM, Stanley NM, Bartley GB. A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves' ophthalmopathy. Ophthalmology. 2001 Sep;108(9):1523-34. doi: 10.1016/s0161-6420(01)00632-7.

  PMID: 11535445 BACKGROUND

• Bartley GB, Gorman CA. Diagnostic criteria for Graves' ophthalmopathy. Am J Ophthalmol. 1995 Jun;119(6):792-5. doi: 10.1016/s0002-9394(14)72787-4.

  PMID: 7785696 BACKGROUND

• Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Measuring eye movements in Graves ophthalmopathy. Ophthalmology. 1994 Aug;101(8):1341-6. doi: 10.1016/s0161-6420(94)31164-x.

  PMID: 8058278 BACKGROUND

• Nugent RA, Belkin RI, Neigel JM, Rootman J, Robertson WD, Spinelli J, Graeb DA. Graves orbitopathy: correlation of CT and clinical findings. Radiology. 1990 Dec;177(3):675-82. doi: 10.1148/radiology.177.3.2243967.

  PMID: 2243967 BACKGROUND

• Kao SC, Kendler DL, Nugent RA, Adler JS, Rootman J. Radiotherapy in the management of thyroid orbitopathy. Computed tomography and clinical outcomes. Arch Ophthalmol. 1993 Jun;111(6):819-23. doi: 10.1001/archopht.1993.01090060107032.

  PMID: 8512483 BACKGROUND

• Prummel MF, Gerding MN, Zonneveld FW, Wiersinga WM. The usefulness of quantitative orbital magnetic resonance imaging in Graves' ophthalmopathy. Clin Endocrinol (Oxf). 2001 Feb;54(2):205-9. doi: 10.1046/j.1365-2265.2001.01220.x.

  PMID: 11207635 BACKGROUND

• Shen S, Fong KS, Wong HB, Looi A, Chan LL, Rootman J, Seah LL. Normative measurements of the Chinese extraocular musculature by high-field magnetic resonance imaging. Invest Ophthalmol Vis Sci. 2010 Feb;51(2):631-6. doi: 10.1167/iovs.09-3614. Epub 2009 Jul 30.

  PMID: 19643971 DERIVED

MeSH Terms

Conditions

Graves Ophthalmopathy

Condition Hierarchy (Ancestors)

Eye Diseases, Hereditary; Eye Diseases; Graves Disease; Exophthalmos; Orbital Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Goiter; Thyroid Diseases; Endocrine System Diseases; Hyperthyroidism; Autoimmune Diseases; Immune System Diseases

Study Officials

• Lay Leng Seah, MMed(Ophth), FRCS(Ed)

  Singapore National Eye Centre

  STUDY CHAIR

• Audrey Lee Geok Looi, MMed(Ophth), FRCS(Ed)

  Singapore National Eye Centre

  PRINCIPAL INVESTIGATOR

• Jack Rootman, MD. FRCS(C)

  University of British Columbia

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV

Study Record Dates

• First Submitted: July 3, 2006
• First Posted: July 4, 2006
• Study Start: June 1, 2003
• Primary Completion: July 1, 2008
• Study Completion: July 1, 2008
• Last Updated: May 12, 2010

Record last verified: 2010-05

Locations

SG (1)