Combined Radiotherapy and Intravenous Steroids for Early Progressive Thyroid Eye Disease (CRISEPTED)

Thyroid eye disease is an autoimmune disorder affecting approximately 50% of individuals with autoimmune thyroid diseases resulting in enlargement of ocular muscles and may lead to congestion of the eyelids and ocular surface, ocular movement restriction and double vision, and optic nerve compression and loss of vision.

First line medical therapy is oral or intravenous corticosteroids (CS), which several studies have shown results in reduction of soft tissue congestion, but some studies suggesting that ocular restriction or visual loss may still occur in spite of CS therapy.i

External beam radiotherapy (XRT) is second line therapy but is controversial, with some studies suggesting benefit in preventing onset of double vision or optic nerve compression while other studies suggest it has no benefit. Most proponents of XRT for TED believe that it is most effective early in the disease evolution. XRT has been shown to be a safe therapy with few side-effects, although retinopathy changes have developed in a small percentage of diabetics and its use is avoided for diabetics.

Combined oral prednisone and XRT has been shown to be more effective in reducing soft tissue inflammation and motility complications than either monotherapy in two different studies.

To date there have been no trials comparing combined XRT and iv CS with iv CS alone for early progressive TED to identify potential benefit in reducing the severity of motility disorders or preventing the onset of dysthyroid optic neuropathy. That is the purpose of this study.

Study Overview

• Status: Unknown
• Conditions: Graves Ophthalmopathy
• Intervention / Treatment: Radiation: External beam radiotherapy; Drug: intravenous corticosteroids (methylprednisolone)

Detailed Description

1. Purpose: To demonstrate that combined Radiotherapy (RT) and intravenous corticosteroid (CS) is more effective than iv CS alone in preventing severe motility disruption (including strabismus and primary diplopia) and new-onset dysthyroid optic neuropathy in early progressive thyroid orbitopathy.
2. Hypothesis: Combined RT and iv CS are more effective than iv CS alone in preventing motility problems (reduced field of single binocular vision, reduced ductions, strabismus and worsening diplopia) and in preventing new-onset dysthyroid optic neuropathy in patients with early progressive thyroid orbitopathy.
3. Justification: Standard therapy for progressive TED is iv CS, occasionally supplemented with RT if complications develop in spite of appropriate iv CS therapy. A single retrospective study suggested that early combined treatment may prevent more serious visual complications; this would be the first randomized controlled prospective trial to see if this finding is true.
4. Objectives: Demonstrate a statistically significant reduced rate of new onset optic neuropathy and double vision in patients with progressive TED with combined therapy versus traditional monotherapy.
5. Research Method: Multicentre, institutional based, randomized controlled trial.
6. Statistical Analysis:

Subjects: 100 patients with early progressive TED randomized equally into two groups:

1. Therapy: iv MP 500 mg iv weekly for 6 weeks, then 250 mg iv weekly for 6 weeks

   + XRT 100 Rads to each orbit x 10 doses

2. Control: Same iv MP dose + no XRT

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 4

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Active TED: Onset less than 6 months AND: Progressive with historic or measured worsening in one or more of VISA parameters in past 2 months: (increasing soft tissue inflammatory changes, development of intermittent or constant diplopia or increased prominence of either eye or lid retraction)
2. Moderately severe TED (all of the following criteria must be met):

V: No optic neuropathy I: Inflammatory score >/= 4/10 S: Intermittent or constant diplopia in any direction except primary gaze AND/OR restriction in ductions to < 30 degrees in any cardinal direction on clinical examination

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Exclusion Criteria:

1. Age < 35 yrs
2. Diabetes mellitus
3. Previous orbital surgery or radiotherapy for TED
4. Corticosteroid or immunotherapy within previous 2 months for TED
5. Unable or unwilling to provide informed consent-

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Combined radiotherapy and iv corticosteroid; Therapy: iv MP 500 mg iv weekly for 6 weeks, then 250 mg iv weekly for 6 weeks + External beam radiotherapy: 100 Rads to each orbit x 10 doses	Radiation: External beam radiotherapy; 100 Rads to each lateral orbit x 10 doses; Drug: intravenous corticosteroids (methylprednisolone); Intravenous methylprednisolone (iv MP) 500 mg weekly x 6 weeks, then iv MP 250 mg x 6 weeks
Active Comparator: iv Corticosteroid; iv MP 500 mg iv weekly for 6 weeks, then 250 mg iv weekly for 6 week No Radiotherapy administered	Drug: intravenous corticosteroids (methylprednisolone); Intravenous methylprednisolone (iv MP) 500 mg weekly x 6 weeks, then iv MP 250 mg x 6 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
New onset dysthyroid optic neuropathy		1 year
Progression in ocular motility dysfunction (Improvement or worsening in motility scores and ocular restriction, and need for strabismus surgery)	Improvement or worsening in motility scores and ocular restriction, and need for strabismus surgery at 1 year following initiation of treatment	1 year
Participants escaping trial (Number of participants leaving trial because of onset of optic neuropathy or primary strabismus)	Number of participants leaving trial because of onset of optic neuropathy or primary strabismus	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
VISA inflammatory scores	Ocular Inflammatory and congestive scores	6 months and 1 year
Quality of life scores	Specific Graves orbitopathy quality of life scoring systems: TED QOL and GO QOL	6 months and 1 year
Proptosis and eyelid retraction changes	Change in proptosis and upper lid retraction	1 year
Supplemental iv corticosteroid requirements	Need for additional intravenous corticosteroids	1 year

Collaborators and Investigators

• Sponsor: University of British Columbia
• Investigators: Principal Investigator: Peter J Dolman, MD, FRCSC, University of British Columbia

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Anticipated): December 1, 2018
• Study Completion (Anticipated): December 1, 2019

Study Registration Dates

• First Submitted: January 12, 2015
• First Submitted That Met QC Criteria: January 14, 2015
• First Posted (Estimate): January 15, 2015

Study Record Updates

• Last Update Posted (Estimate): January 15, 2015
• Last Update Submitted That Met QC Criteria: January 14, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Genetic Diseases, Inborn; Thyroid Diseases; Eye Diseases, Hereditary; Graves Disease; Exophthalmos; Orbital Diseases; Goiter; Hyperthyroidism; Eye Diseases; Graves Ophthalmopathy; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate
• Other Study ID Numbers: H14-03166