Clinical trial NCT02845336
Conditions: Thyroid Eye Disease
Sponsor: Johns Hopkins University
Start date: 2017-03-05; Completion date: 2019-06-30
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Thyroid eye disease (TED) is an autoimmune disorder in which the immune system attacks orbital tissues, resulting in characteristic changes in eyelid position, globe position in the orbit, extraocular muscle balance, and optic nerve function. TED is a potentially blinding disease, and current treatments largely consist of nonspecific reduction of inflammation using corticosteroids or radiation therapy. Regardless of treatment, once TED progresses from its inflammatory phase to a more fibrotic, resolution phase, the orbital changes become fixed and can be modified only by surgery.

The investigators propose to treat a cohort of patients with active TED using a selective COX-2 inhibitor, celecoxib, and to compare these patients to an observational control group. The investigators hypothesize that celecoxib will reduce the severity of disease and/or prevent progression to proptosis, diplopia, and corneal exposure or compressive optic neuropathy.

Detailed description:
The investigators intend to use celecoxib, a non-steroidal anti-inflammatory drug approved by the Food and Drug Administration (FDA) for the treatment of pain, osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, as a treatment for active TED. In vitro data have shown that transformation of orbital fibroblasts into adipocytes is mediated by cyclooxygenase-2 (COX-2), and a case report suggests that COX-2 inhibition can improve TED in the acute phase. Thus, the investigators intend to evaluate the efficacy of COX-2 inhibition in the treatment of active TED and its ability to improve both the acute inflammatory signs and more permanent fibrotic changes of quiescent disease. The investigators will enroll patients with active TED and treat them for 3 months (a characteristic period of disease activity) and compare this to standard treatments for mild active TED (observation, with over the counter interventions such as lubrication with artificial tears) to assess efficacy.

Arms: arm 1: Patients who are randomized to treatment with celecoxib 100mg pills by mouth twice a day for 3 months, in addition to standard of care treatment as described under the Control arm arm 2: Patients who are randomized to standard treatment (requiring no prescription medication, but standard recommendations such as artificial tears, avoiding cigarette smoke)
Interventions: intervention 1: Celecoxib intervention 2: artificial tears
Intervention descriptions: intervention 1: celecoxib 100mg PO twice per day for 3 months intervention 2: Standard care for mild thyroid eye disease is lubrication with artificial tears (over the counter), avoidance of cigarette smoke.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
TITLE: Celecoxib for Thyroid Eye Disease 
 
NCT: 02845336 
 
PI: Timothy McCulley 
 
DATE: January 21, 2017 


Date: January 21, 2017 
Principal Investigator: Timothy McCulley 
Application Number: IRB00094787 
 
 
 
 
 
 
JHM IRB - eForm A – Protocol 
 
 
 
 Use the section headings to write the JHM IRB eForm A, inserting the appropriate material in 
each. If a section is not applicable, leave heading in and insert N/A. 
 When submitting JHM IRB eForm A (new or revised), enter the date submitted to the field at the 
top of JHM IRB eForm A. 
 
*************************************************************************************************** 
 
 
1. 
Abstract 
 
o Thyroid eye disease (TED) is an autoimmume disorder in which autoantibodies against the TSH 
receptor attack orbital tissues, resulting in characteristic changes in eyelid position, globe 
position in the orbit, extraocular muscle balance, and optic nerve function. TED is a potentially 
blinding disease, and current treatments largely consist of nonspecific reduction of inflammation 
using corticosteroids or radiation therapy. The former treatment has significant morbidity, while 
the latter is controversial. Rituximab, which depletes CD20+ cells, has been used recently in 
severe disease but has evoked concern because of its cost and potential morbidity. Regardless of 
treatment, once TED progresses from its inflammatory phase to a more fibrotic, resolution phase, 
the orbital changes become fixed and can be modified only by surgery. We intend to use 
celecoxib (Celebrex), a non-steroidal anti-inflammatory drug approved by the Food and Drug 
Administration (FDA) for the treatment of pain, osteoarthritis, rheumatoid arthritis, and 
ankylosing spondylitis, as a treatment for active TED. In vitro data have shown that 
transformation of orbital fibroblasts into adipocytes is mediated by cyclooxygenase-2 (COX-2) 
via the PPAR-gamma pathway, and a single case report suggests that COX-2 inhibition can 
improve TED in the acute phase. Thus, we intend to evaluate the efficacy of COX-2 inhibition in 
the treatment of active TED and its ability to improve both the acute inflammatory signs and 
more permanent fibrotic changes of quiescent disease. We will enroll patients with active TED 
and treat them for 3 months (a characteristic period of disease activity) and compare this to 
standard treatments for mild TED (observation with only over the counter interventions such as 
lubrication with artificial tears) to assess efficacy. 
 
2. 
Objectives (include all primary and secondary objectives) 
 
o Study the effectiveness of celecoxib (Celebrex) in the reduction of orbital inflammation in 
patients with thyroid eye disease. 
o Primary outcome- reduction of clinical activity (by Clinical Activity Score (CAS) and 
VISA score (Vision, Inflammation, Strabismus, Appearance)) 
o Secondary outcomes- improvement in proptosis, strabismus, and eyelid retraction, and 
TED quality of life questionnaire 
 
3. 
Background 


Date: January 21, 2017 
Principal Investigator: Timothy McCulley 
Application Number: IRB00094787 
 
 
 
 
o Thyroid eye disease (TED) occurs in up to 50% of patients with Graves disease and to a lesser 
extent in Hashimoto thyroiditis. Autoantibodies to the TSH receptor [thyroid stimulating 
immunoglobulin (TSI) and TSH receptor antibody (TSHR Ab)] have cross-reactivity with 
similar antigens on the surface of orbital cell membranes. The basic pathogenesis of TED 
involves a cell-mediated inflammatory process that attacks orbital soft tissues, including 
adipocytes, fibroblasts, and extraocular muscle. Their binding results in recruitment of T-cells 
and monocytes (and B-cells to a lesser extent) and secretion of inflammatory cytokines. After an 
acute inflammatory phase, a chronic condition results from persistent tissue changes including 
extraocular muscle fibrosis and fat hypertrophy. Vision problems result when adipocyte 
proliferation leads to proptosis and corneal exposure, and extraocular muscle enlargement in 
addition to adipogenesis can cause compressive optic neuropathy. Proptosis is also disfiguring 
and can be remedied only by surgery after the inflammatory phase resolves; this can take 1-2 
years without any medical intervention. Chronic TED responds only to surgical correction, and 
treatment in the acute phase can reduce morbidity. Current treatments of active TED involve 
nonspecific anti-inflammatory medications such as corticosteroids (with the attendant side 
effects) and orbital radiotherapy (controversial because of limited data supporting efficacy and 
theoretic risk of secondary malignancy).  Recently, rituximab has been used in severe cases, but 
its expense and side effect profile have limited its utility. 
o In addition to cytokines, activated T-cells produce ligands for peroxisome proliferator activated 
receptor (PPAR) gamma. These ligands include prostaglandins created via the cyclooxeganse-2 
(COX-2) pathway. PPAR-gamma activation has been implicated in systemic adipogenesis in 
patients taking thiazolidinedione drugs for glycemic control, and in vitro studies of cultured 
orbital fibroblasts have shown that exposing cells to PPAR-gamma ligands such as specific 
prostaglandin analogues results in transformation of fibroblasts into adipocytes. This effect is 
more robust with TED fibroblasts than in cells isolated from control patients. Inhibiting the 
PPAR-gamma pathway in vitro with a selective COX-2 inhibitor blocks fibroblast 
transformation. A single case report in the literature also supports the possible in vivo efficacy 
of COX-2 inhibition in active TED. 
o Based on these in vitro and in vivo findings, we propose to treat a cohort of patients with active 
TED using a selective COX-2 inhibitor, celecoxib (Celebrex), and to compare these patients to 
an observational control group. We hypothesize that celecoxib will reduce the severity of 
disease and/or prevent progression to proptosis, diplopia, and corneal exposure or compressive 
optic neuropathy. We will assess the effect of the treatment using validated clinical scoring 
tools, including the Clinical Activity Scale (CAS) from the European Graves Orbitopathy Group 
(EUGOGO) and the VISA (vision, inflammation, strabismus, appearance) scale of the 
International Thyroid Eye Disease Study (ITEDS) group.   We will also use a validated Graves 
ophthalmopathy quality of life survey as a secondary outcome measure.  Outcomes will be 
assessed at timepoints noted below with a 3-month period of treatment and follow-up for 1 year.  
 
4. 
Study Procedures 
o Patients will be recruited from the Wilmer Eye Institute practices of the investigators. 
o The exam will include a thorough history including a list a medications, health conditions 
previous surgeries and medical allergies (standard of care). 
 
o The complete eye examination will measure visual acuity, eye movements (sensorimotor exam), 
visual fields, proptosis, pupil function, anterior segment evaluation, and lastly dilated fundus 


Date: January 21, 2017 
Principal Investigator: Timothy McCulley 
Application Number: IRB00094787 
 
 
 
 
exam to evaluate the potential subject’s optic nerve.  Photographs (external, eye movements, 
optic nerve) may be taken as needed.  This eye examination is standard of care on any thyroid 
eye disease patient. Findings from the eye exam will be used to determine a CAS and VISA 
score. The CAS takes into account 7 manifestations (spontaneous retrobulbar pain, pain with eye 
movement, eyelid erythema, eyelid edema, conjunctival injection, chemosis, and caruncular 
swelling) with 1 point assigned for each positive finding. The VISA score ranges from 0-16 
based on findings related to inflammation, strabismus, and eyelid changes and proptosis 
(appearance). Both scales were developed to assess features of active disease that might change 
with treatment. 
 
o Study subjects will be randomly assigned to observation with no prescription treatment, or 
treatment with oral celecoxib 100 mg twice daily for 3 months.  Patients will have a full clinical 
exam at baseline, 1 month, 3 months, 6 months, and 12 months, with additional clinical visits 
more frequently if indicated by disease course/activity.  The proposed frequency of clinic visits 
is within standard of care for newly diagnosed active-phase TED.   
 
o For those subjects randomized to the treatment group, baseline blood testing for blood counts, 
renal and hepatic function (BUN, Cr, AST, ALT, total bilirubin) will be obtained prior to starting 
the drug. Testing will be performed by a standard clinical laboratory and billed to insurance. 
Testing will be repeated at 1mo and 3mo after randomization/initiation of therapy for those 
receiving celecoxib. Abnormal BUN or creatinine (outside normal range) on lab testing or any 
previous/current kidney disease will be the criteria for labeling a patient as having impaired renal 
function.  Abnormal liver enzymes (AST, ALT, bilirubin outside normal range) or 
previous/current liver disease will determine whether a patient is labeled as having impaired 
hepatic function. Monthly phone interviews also will be conducted by physician study team 
members to determine if other side effects, such as edema, may be occurring. Subjects will be 
asked specifically about peripheral swelling, any blood in urine or skin discoloration, or changes 
in exercise tolerance. Positive responses will trigger an unscheduled visit with the PI or co-
investigator MD. Patients will be cautioned not to take additional NSAID medications while on 
Celecoxib, as this may increase the chance for adverse effects. 
 
o Outcomes: The primary study outcome is reduction of clinical activity of TED, as determined by 
both the CAS and VISA scores. We will use both scales because there is currently disagreement 
as to which scale serves as a better overall assessment tool. Secondary outcome measures will 
include reduction of specific aspects of TED, including proptosis, diplopia, and eyelid retraction, 
as well as a validated TED-specific quality of life survey. These elements are captured in part by 
the 2 scales but also will be evaluated separately.  Comparison of our primary and secondary 
outcomes between the treatment and control groups and with published studies of steroid 
treatment for TED may provide us with an indication of the relative efficacy of celecoxib 
treatment and whether further study is warranted. Treatment safety also will be assessed, and 
adverse events recorded. A recent prospective study of intravenous corticosteroid dosing for 
TED reported major adverse events in 10/159 (6.3%) of subjects and minor adverse events such 
as gastric distress, mild BP increase not requiring medication, and local skin reactions in about 
25% of subjects. We anticipate a lesser incidence of minor or major adverse events based on the 
side effect profile of celecoxib in patients without co-morbidities placing them at higher risk 
(most TED patients are young and otherwise healthy). Occurrence of adverse events at a rate 


Date: January 21, 2017 
Principal Investigator: Timothy McCulley 
Application Number: IRB00094787 
 
 
 
 
greater than what has been reported for intravenous corticosteroid (an accepted method of TED 
treatment) would suggest that risk of celecoxib treatment exceeds any benefit. 
 
o Biospecimens will be collected in this study, to include urine for a pregnancy test for female 
patients of childbearing age to determine eligibility, as well as blood as noted above that will be 
drawn by the clinical lab. 
 
 
 
 
o Study length: Subjects will be followed for 12 months. 
 
o Safety monitoring: As noted, baseline blood testing and phone surveillance will be performed. If 
abnormal results are found during drug treatment, then subjects will be advised to stop the 
medication and will be examined by the PI or other MD investigator.  Adverse events will be 
reported to the IRB per institutional policy.  
 
o Subjects may be taken out of the study if: 
 Staying in the study would be harmful. 
 Treatment required is not allowed in the study. 
 Those that fail to follow instructions. 
 Subjects become pregnant. 
 The study is cancelled. 
 There may be other reasons to take subjects out of the study that we do not know at this 
time.  
 
 
5. 
Inclusion/Exclusion Criteria 
 
Eligibility criteria: 
 Recent diagnosis of thyroid eye disease (within the past 6 months) 
 Have ocular symptoms or signs of TED with a CAS score of at least 3 
 Ages 18-80 years 
 
Exclusion criteria: 
 Pregnancy 
 Previous treatment with corticosteroid for TED for >2wks 
 Previous treatment with orbital radiation for TED 
 Impaired renal function 
 Impaired hepatic function 
 Treatment with antihypertensive medications except beta-blockers 
 History of congestive heart failure, cardiac valvular disease, or coronary artery disease 
 Allergy to NSAID or previous adverse reaction (ie. GI bleeding) 
 Vision loss due to compressive optic neuropathy 
 
Target 40 participants will be enrolled in this study.  
 
 


Date: January 21, 2017 
Principal Investigator: Timothy McCulley 
Application Number: IRB00094787 
 
 
 
 
6. 
Drugs/ Substances/ Devices 
Celecoxib (Celebrex) is a non-steroidal anti-inflammatory drug approved by the Food and Drug 
Administration (FDA) for the treatment of pain, osteoarthritis, rheumatoid arthritis, and ankylosing 
spondylitis. We will be using the recommended dosage of 100 mg twice a day over the course of 3 
months.  Celecoxib for TED is an off-label usage. 
 
7. 
Study Statistics 
The primary study outcome is reduction of clinical activity of TED, as determined by both the CAS and 
VISA scores. We will use both scales because there is currently disagreement as to which scale serves 
as a better overall assessment tool. Secondary outcome measures will include reduction of specific 
aspects of TED, including proptosis, diplopia, and eyelid retraction. These elements are captured in part 
by the 2 scales but also will be evaluated separately. Change in quality of life will be measured by a 
validated questionnaire as another secondary outcome measure. Comparison of our primary outcomes 
between treatment and control groups will provide us with an indication of the relative efficacy of 
celecoxib treatment. Treatment safety also will be assessed, and adverse events recorded. A recent 
prospective study of intravenous corticosteroid dosing for TRO reported major adverse events in 
10/159 (6.3%) of subjects and minor adverse events such as gastric distress, mild BP increase not 
requiring medication, and local skin reactions in about 25% of subjects. We anticipate a lesser 
incidence of minor or major adverse events based on the side effect profile of celecoxib in patients 
without co-morbidities placing them at higher risk (most TED patients are young and otherwise 
healthy). Occurrence of adverse events at a rate greater than what has been reported for intravenous 
corticosteroid (an accepted method of TED treatment) would suggest that risk of celecoxib treatment 
exceeds any benefit. Observation of adverse events in excess of this rate during the treatment phase 
would require review, and consideration of early study termination. The changes in either the CAS or 
VISA score will be compared between the celecoxib and observation groups to determine whether a 
trend or significant difference can be found. 
 
8. 
Risks 
The study procedures, apart from the proposed treatment, carry no risk beyond that of standard clinical 
care. Celecoxib has well-described risks especially in certain patient populations, who will be excluded 
from this study as noted. Below is an enumeration of risks copied from the package insert: 
 
Cardiovascular warning: All prescription NSAIDs, like CELEBREX, ibuprofen, naproxen, and 
meloxicam have the same cardiovascular warning. They may all increase the chance of heart attack 
or stroke that can lead to death. This chance increases if you have heart disease or risk factors for it, 
such as high blood pressure or when NSAIDs are taken for long periods. Congestive heart failure 
and peripheral edema has also occurred in some patients has also been noted.  
 
CELEBREX should not be used right before or after certain heart surgeries.  
 
Stomach and intestine risk: All prescription NSAIDs have the same warning for serious stomach 
and intestine problems: They may cause ulcers and bleeding, which can occur without warning and 
may cause death.  
 
Renal warning: Long term use of NSAIDs, like CELEBREX, have resulted in renal papillary 
necrosis.  Patients at risk are those with impaired renal function, heart failure, liver dysfunction, 
those taking diuretics, ACE inhibitors, and angiotension II inhibitors. 


Date: January 21, 2017 
Principal Investigator: Timothy McCulley 
Application Number: IRB00094787 
 
 
 
 
 
Serious skin and allergic reactions can occur with CELEBREX. CELEBREX shold not be taken 
if one has had an asthma attack, hives, or other allergies to aspirin, other NSAIDs, or certain drugs 
called sulfonamides.  
Risks of corticosteroid treatment are noted in section 7 with at least 25% of patients experiencing a 
minor or major adverse event. Orbital radiotherapy carries theoretic risk of ocular radiation toxicity 
(cataract formation, radiation retinopathy or optic neuropathy) and second malignancy occurrence, but 
the actual rate of such events is not known. Untreated, some patients with TED may have spontaneous 
improvement while others will progress to more severe manifestations. Increased disease activity at 
presentation is a predictor for progression, and we thus are including only subjects with clinical activity 
that may put them at risk for such changes. Treatment is effective only during the active phase of TED, 
and observation may result in irreversible proptosis or strabismus requiring subsequent surgery. 
9. 
Benefits 
The major benefit of the study is anticipated to be reduction of TED severity as measured by clinical 
activity assessment. 
 
10. 
Payment and Remuneration 
Subjects will not be compensated for participation. 
 
11. 
Costs 
Subjects will receive a separate Insurance and Research Participant Financial Responsibility Information 
Sheet (Sheet).  
 
This Sheet will give subjects the following information: 
 
o The drugs that are part of this research will be paid for by their insurance  
o The required laboratory testing will be paid for by their insurance 
o The standard eye examination, procedures and tests that will be performed will be billed to the 
subject and/or their health insurer.  Subjects with health insurance will be responsible for any co-
pays or deductibles not covered by their insurance.   All planned visits with standard testing are 
consistent with standard of care and will be charged to insurance as usual.