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

• ClinicalTrials.gov Identifier: NCT02339142
• Recruitment Status: Not yet recruiting
• First Posted: January 15, 2015
• Last Update Posted: January 15, 2015
• Sponsor: University of British Columbia
• Information provided by (Responsible Party): Peter Dolman, University of British Columbia

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Graves Ophthalmopathy	Radiation: External beam radiotherapy; Drug: intravenous corticosteroids (methylprednisolone)	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Combined Radiotherapy and Intravenous Steroids for Early Progressive Thyroid Eye Disease
• Study Start Date: January 2015
• Estimated Primary Completion Date: December 2018
• Estimated Study Completion Date: December 2019

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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

-

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-

Contacts and Locations

Contacts

Contact: Peter J Dolman, MD, FRCSC; 604 306 4482; peterdolman@hotmail.com

Contact: Wilfredo Yap; 604 875-4346 ext 2; lemontree604@yahoo.com

Sponsors and Collaborators

University of British Columbia

Investigators

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

More Information

• Responsible Party: Peter Dolman, Clinical Professor, University of British Columbia
• ClinicalTrials.gov Identifier: NCT02339142 History of Changes
• Other Study ID Numbers: H14-03166
• First Posted: January 15, 2015
• Last Update Posted: January 15, 2015
• Last Verified: January 2015

Additional relevant MeSH terms:

Graves Ophthalmopathy; Eye Diseases; 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; Prednisolone hemisuccinate; Prednisolone phosphate; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuroprotective Agents