Doxycycline Treatment in Mild Thyroid-Associated Ophthalmopathy

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

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).

Study Overview

• Status: Recruiting
• Conditions: Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Thyroid Diseases; Eye Diseases, Hereditary; Graves Ophthalmopathy; Graves Disease; Hyperthyroidism; Thyroid-associated Ophthalmopathy
• Intervention / Treatment: Drug: Doxycycline hyclate; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Dan Liang, MD; Phone Number: 0086-20-87331766; Email: linml0754@gmail.com

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510060
      • Recruiting
      • Zhongshan Ophthalmic Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Doxycycline; Tablets Doxycycline 50 mg PO per day for 12 weeks	Drug: Doxycycline hyclate; Tab. Doxycycline 50 mg PO per day for 12 weeks
Placebo Comparator: Placebo; Tablet placebo for 12 weeks	Drug: Placebo; Tablet placebo for 12 weeks

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

Collaborators and Investigators

• Sponsor: Sun Yat-sen University
• Investigators: Principal Investigator: Dan Liang, MD, Zhongsh Ophthalmic Center

Publications and helpful links

General Publications

• Pan Y, Chen YX, Zhang J, Lin ML, Liu GM, Xu XL, Fan XQ, Zhong Y, Li Q, Ai SM, Xu W, Tan J, Zhou HF, Xu DD, Zhang HY, Xu B, Wang S, Ma JJ, Zhang S, Gan LY, Cui JT, Li L, Xie YY, Guo X, Pan-Doh N, Zhu ZT, Lu Y, Shi YX, Xia YW, Li ZY, Liang D. Doxycycline vs Placebo at 12 Weeks in Patients With Mild Thyroid-Associated Ophthalmopathy: A Randomized Clinical Trial. JAMA Ophthalmol. 2022 Nov 1;140(11):1076-1083. doi: 10.1001/jamaophthalmol.2022.3779.

Study record dates

Study Major Dates

• Study Start: July 1, 2014
• Primary Completion (Anticipated): July 1, 2022
• Study Completion (Anticipated): July 1, 2022

Study Registration Dates

• First Submitted: July 28, 2014
• First Submitted That Met QC Criteria: July 28, 2014
• First Posted (Estimate): July 30, 2014

Study Record Updates

• Last Update Posted (Actual): November 17, 2021
• Last Update Submitted That Met QC Criteria: November 16, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Thyroid eye disease; Thyroid-associated ophthalmopathy; Doxycycline; Graves' orbitopathy; Graves´ ophthalmopathy; EUGOGO; CAS
• Additional Relevant MeSH Terms: Exophthalmos; Orbital Diseases; Goiter; Eye Diseases; Graves Ophthalmopathy; Thyroid Diseases; Hyperthyroidism; Autoimmune Diseases; Endocrine System Diseases; Immune System Diseases; Genetic Diseases, Inborn; Graves Disease; Eye Diseases, Hereditary; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Doxycycline
• Other Study ID Numbers: 2013MEKY033