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Thyroid Treatment Trial

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ClinicalTrials.gov Identifier: NCT00348413
Recruitment Status : Completed
First Posted : July 4, 2006
Last Update Posted : May 12, 2010
Sponsor:
Collaborator:
International Stem Cell Forum
Information provided by:
Singapore National Eye Centre

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).


Condition or disease Intervention/treatment Phase
Graves Ophthalmopathy Drug: Intravenous Methylprednisolone + Oral Methotrexate vs Intravenous Methylprednisolone + Placebo Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double
Primary Purpose: Treatment
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.
Study Start Date : June 2003
Actual Primary Completion Date : July 2008
Actual Study Completion Date : July 2008





Primary Outcome Measures :
  1. Inflammatory index

Secondary Outcome Measures :
  1. Motility
  2. Proptosis


Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. 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)

    OR

    - Thyroid dysfunction or abnormal regulation in association with any one of the following:

    -Exophthalmos

    - Extraocular muscle involvement

    - Optic nerve dysfunction

  2. Active disease

Inflammatory Index

Inflammatory Index

Soft tissue feature Rating Chemosis 0 Absent

  1. Moderate (up to lid margin)
  2. Severe (over lid margin; persists on closing eye)

Conjunctival injection 0 Absent 1 Present

Lid injection 0 Absent

1 Present

Lid edema 0 Absent

  1. Moderate
  2. Severe (festoons, overhang)

Pain at rest (clearly defined as retrobulbar aching) 0 Absent 1 Present

Pain on movement 0 Absent

1 Present

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 20.

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

Exclusion Criteria:

  1. Previous treatment for TED

    • Oral steroids (e.g. immunosuppressive dose) for last 3 months, radiotherapy
    • Intravenous pulsed steroid or methrotrexate therapy
  2. 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)
  3. 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
    • History of seizure
    • History of mental / psychiatric disorder
    • Patients with clinical features of optic nerve disc pallor at primary presentation will be excluded

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00348413


Locations
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Singapore
Singapore National Centre
Singapore, Singapore, 168751
Sponsors and Collaborators
Singapore National Eye Centre
International Stem Cell Forum
Investigators
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Study Chair: Lay Leng Seah, MMed(Ophth), FRCS(Ed) Singapore National Eye Centre
Principal Investigator: Audrey Lee Geok Looi, MMed(Ophth), FRCS(Ed) Singapore National Eye Centre
Principal Investigator: Jack Rootman, MD. FRCS(C) University of British Columbia
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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ClinicalTrials.gov Identifier: NCT00348413    
Other Study ID Numbers: R272/16/2002
First Posted: July 4, 2006    Key Record Dates
Last Update Posted: May 12, 2010
Last Verified: May 2010
Keywords provided by Singapore National Eye Centre:
Graves ophthalmopathy/therapy
Randomized controlled trial
Methylprednisolone
Methotrexate
Additional relevant MeSH terms:
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Eye Diseases
Graves Ophthalmopathy
Eye Diseases, Hereditary
Graves Disease
Exophthalmos
Orbital Diseases
Genetic Diseases, Inborn
Goiter
Thyroid Diseases
Endocrine System Diseases
Hyperthyroidism
Autoimmune Diseases
Immune System Diseases
Methylprednisolone
Methylprednisolone Acetate
Methylprednisolone Hemisuccinate
Prednisolone
Prednisolone acetate
Methotrexate
Prednisolone hemisuccinate
Prednisolone phosphate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents