Doxycycline Treatment in Mild Thyroid-Associated Ophthalmopathy

Study Overview
=================
Brief Summary
-----------------
The aim of this study is to evaluate the effects of subantimicrobial dose doxycycline (50 mg/d), administered for 12 weeks, on patients with mild Thyroid-Associated Ophthalmopathy (TAO).

Detailed Description
-----------------
Thyroid-Associated Ophthalmopathy is an autoimmune disease that can be treated by corticosteroids and surgery. But they often cause severe side-effects and are usually used for treating moderate-sever and sight-threatening TAO. Wait and see will be the first choice for the patient with mild TAO. Subantimicrobial dose (SD) doxycycline displays a strong anti-inflammatory and immunomodulatory function, which is independent of its antibiotic properties. Data from clinical trials demonstrated that SD doxycycline was effective in moderating inflammation in a variety of autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, rosacea and periodontitis. We propose to test the effect of subantimicrobial dose doxycycline for mild TAO.

Official Title
-----------------
The Effect of Subantimicrobial Dose Doxycycline in Mild Thyroid-Associated Ophthalmopathy

Conditions
-----------------
Thyroid Diseases, Endocrine System Diseases, Eye Diseases, Hereditary, Hyperthyroidism, Autoimmune Diseases, Immune System Diseases, Graves Ophthalmopathy, Graves Disease, Thyroid-associated Ophthalmopathy

Intervention / Treatment
-----------------
* Drug: Doxycycline hyclate
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Clinical diagnosis of Thyroid-associated ophthalmopathy Mild TAO Normal serum free thyroxine and free triiodothyronine concentrations No previous specific therapy for TAO, except for local measures Written informed consent is obtained Exclusion Criteria: Pregnant females as determined by positive (serum or urine) hCG test at screening or prior to dosing, or lactating females Uncontrolled diabetes or hypertension History of mental / psychiatric disorder 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) Tetracycline allergy or intolerance

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doxycycline<br>Tablets Doxycycline 50 mg PO per day for 12 weeks | Drug: Doxycycline hyclate<br>* Tab. Doxycycline 50 mg PO per day for 12 weeks<br>|
| Placebo Comparator: Placebo<br>Tablet placebo for 12 weeks | Drug: Placebo<br>* Tablet placebo for 12 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the rate of improvement | Improvement was defined that at least one item was met in the study eye without deterioration in any item of both eyes: reduction of eyelid aperture by at least 2mm; reduction in exophthalmos by at least 2mm; increase in ocular motility by at least 8 degrees in any duction; increase on either GO-QOL scales by at least 6 points. The higher of the rate of improvement gets, the better the outcome is. The primary outcome ranges from -100% to 100%. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Activity Score (CAS) | Patients will be assessed according to the 7 item European Group on Graves' Ophthalmopathy (EUGOGO) amended Clinical Activity Score (CAS) For each item present, one point is given. The sum of the points is the total score ranges from 0 to 7. Spontaneous orbital pain. Gaze evoked orbital pain. Eyelid swelling that is considered to be due to active (inflammatory phase) GO. Eyelid erythema. Conjunctival redness that is considered to be due to active (inflammatory phase) GO (ignore equivocal redness). Chemosis. Inflammation of caruncle or plica. | 4weeks and 12 weeks | 
| Proptosis measured by Hertel instrument | For the assessment of proptosis, the same Hertel instrument and ideally the same observer should be used on each occasion. Additionally the same intercanthal distance (ICD) should be used on each occasion. The Hertel values will be measured for each eye at each visit and repeated three times. The mean value is recorded. Proptosis ranges from 10mm to 30mm. | 4weeks and 12 weeks | 
| Eyelid aperture | For the assessment of eyelid aperture, the same millimeter ruler should be used by the same observer. These measurements are repeated three times, and the mean value is recorded. When performed this assessment, participants should relax their eyes and keep looking ahead and the observers should keep the ruler perpendicular to their eyelid. | 4weeks and 12 weeks | 
| Lid retraction | For the assessment of eyelid aperture, the same millimeter ruler should be used by the same observer. The upper eyelid positions above (positive value) and below (negative value) the superior limbus and The lower eyelid positions above (positive value) and below (negative value) the posterior limbus were measured in millimeters in primary position. These measurements are repeated three times, and the mean value is recorded. | 4weeks and 12 weeks | 
| Lid lag | For the assessment of eyelid aperture, the same millimeter ruler should be used by the same observer. Lid lag is defined that the lid margin distance in downgaze. The upper eyelid positions above (positive value) and below (negative value) the superior limbus were measured in millimeters. | 4weeks and 12 weeks | 
| Eye motility | The head of each participant is adjusted to fix on the modified perimeter to set the visual axis of the examined eye on the center of the optimal visual target in visual chart. The other eye should be covered. The examined eye should follow the movement of the visual target until the participant cannot identify the exact visual target in vertical and horizontal directions. And the extreme scales of these four directions are obtained. These measurements are repeated three times, and the mean value is recorded. | 4weeks and 12 weeks | 
| Graves' Ophthalmopathy Quality of Life Scale | The Graves' Ophthalmopathy Quality of Life (GO-QOL) questionnaire (Terwee & al, 1998) includes visual functioning and psychosocial functioning. A raw score of each part is calculated by adding each score of 8 question, namely 1, 2, or 3 for each question which means marked, mild, or absent limitation, the final score ranging from 0 (full limitation) to 100 (no limitation) is calculated as the following rule: (raw score - 8) ÷ 16 × 100]. GO-QOL will be completed at screening, weeks 0, 4, 12. were also recorded to assess activity of TAO and impact on quality of life respectively. The GO-QOL is a 16 item self-administered questionnaire used to assess the perceived effects of TAO by the patients on their daily physical and psychosocial functioning. | 4weeks and 12 weeks | 
| C-OSDI | The Ocular Surface Disease Index (OSDI), developed by the Outcomes Research Group at Allergan Inc (Irvine, Calif), is a 12-item questionnaire designed to provide a rapid assessment of the symptoms of ocular irritation and vision-related functioning. | 4weeks and 12 weeks | 
| the category of adverse events and the frequency of the occurrence of adverse events | The category of adverse events and the frequency of the occurrence of adverse events are listed to describe the safety. | 4weeks and 12 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Graves' orbitopathy, Graves´ ophthalmopathy, Thyroid eye disease, Thyroid-associated ophthalmopathy, Doxycycline, EUGOGO, CAS