<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02203682</url>
  </required_header>
  <id_info>
    <org_study_id>2013MEKY033</org_study_id>
    <nct_id>NCT02203682</nct_id>
  </id_info>
  <brief_title>Doxycycline Treatment in Mild Thyroid-Associated Ophthalmopathy</brief_title>
  <official_title>The Effect of Subantimicrobial Dose Doxycycline in Mild Thyroid-Associated Ophthalmopathy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sun Yat-sen University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sun Yat-sen University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim of this study is to evaluate the effects of subantimicrobial dose doxycycline (50&#xD;
      mg/d), administered for 12 weeks, on patients with mild Thyroid-Associated Ophthalmopathy&#xD;
      (TAO).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Thyroid-Associated Ophthalmopathy is an autoimmune disease that can be treated by&#xD;
      corticosteroids and surgery. But they often cause severe side-effects and are usually used&#xD;
      for treating moderate-sever and sight-threatening TAO. Wait and see will be the first choice&#xD;
      for the patient with mild TAO.&#xD;
&#xD;
      Subantimicrobial dose (SD) doxycycline displays a strong anti-inflammatory and&#xD;
      immunomodulatory function, which is independent of its antibiotic properties. Data from&#xD;
      clinical trials demonstrated that SD doxycycline was effective in moderating inflammation in&#xD;
      a variety of autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, rosacea&#xD;
      and periodontitis.&#xD;
&#xD;
      We propose to test the effect of subantimicrobial dose doxycycline for mild TAO.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date>July 2014</start_date>
  <completion_date type="Anticipated">July 2022</completion_date>
  <primary_completion_date type="Anticipated">July 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>the rate of improvement</measure>
    <time_frame>12 weeks</time_frame>
    <description>Improvement was defined that at least one item was met in the study eye without deterioration in any item of both eyes:&#xD;
reduction of eyelid aperture by at least 2mm;&#xD;
reduction in exophthalmos by at least 2mm;&#xD;
increase in ocular motility by at least 8 degrees in any duction;&#xD;
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%.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical Activity Score (CAS)</measure>
    <time_frame>4weeks and 12 weeks</time_frame>
    <description>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.&#xD;
Spontaneous orbital pain.&#xD;
Gaze evoked orbital pain.&#xD;
Eyelid swelling that is considered to be due to active (inflammatory phase) GO.&#xD;
Eyelid erythema.&#xD;
Conjunctival redness that is considered to be due to active (inflammatory phase) GO (ignore &quot;equivocal&quot; redness).&#xD;
Chemosis.&#xD;
Inflammation of caruncle or plica.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proptosis measured by Hertel instrument</measure>
    <time_frame>4weeks and 12 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Eyelid aperture</measure>
    <time_frame>4weeks and 12 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lid retraction</measure>
    <time_frame>4weeks and 12 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lid lag</measure>
    <time_frame>4weeks and 12 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Eye motility</measure>
    <time_frame>4weeks and 12 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Graves' Ophthalmopathy Quality of Life Scale</measure>
    <time_frame>4weeks and 12 weeks</time_frame>
    <description>The Graves' Ophthalmopathy Quality of Life (GO-QOL) questionnaire (Terwee &amp; 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.&#xD;
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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C-OSDI</measure>
    <time_frame>4weeks and 12 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>the category of adverse events and the frequency of the occurrence of adverse events</measure>
    <time_frame>4weeks and 12 weeks</time_frame>
    <description>The category of adverse events and the frequency of the occurrence of adverse events are listed to describe the safety.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Graves Ophthalmopathy</condition>
  <condition>Graves Disease</condition>
  <condition>Thyroid-associated Ophthalmopathy</condition>
  <condition>Thyroid Diseases</condition>
  <condition>Endocrine System Diseases</condition>
  <condition>Eye Diseases, Hereditary</condition>
  <condition>Hyperthyroidism</condition>
  <condition>Autoimmune Diseases</condition>
  <condition>Immune System Diseases</condition>
  <arm_group>
    <arm_group_label>Doxycycline</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tablets Doxycycline 50 mg PO per day for 12 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Tablet placebo for 12 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxycycline hyclate</intervention_name>
    <description>Tab. Doxycycline 50 mg PO per day for 12 weeks</description>
    <arm_group_label>Doxycycline</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Tablet placebo for 12 weeks</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Clinical diagnosis of Thyroid-associated ophthalmopathy&#xD;
&#xD;
          -  Mild TAO&#xD;
&#xD;
          -  Normal serum free thyroxine and free triiodothyronine concentrations&#xD;
&#xD;
          -  No previous specific therapy for TAO, except for local measures&#xD;
&#xD;
          -  Written informed consent is obtained&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant females as determined by positive (serum or urine) hCG test at screening or&#xD;
             prior to dosing, or lactating females&#xD;
&#xD;
          -  Uncontrolled diabetes or hypertension&#xD;
&#xD;
          -  History of mental / psychiatric disorder&#xD;
&#xD;
          -  Hepatic dysfunction (Alb, AST, ALT and Alkaline phosphates levels must be within&#xD;
             normal range for eligibility)&#xD;
&#xD;
          -  Renal impairment (Urea and Creatinine levels must be within normal range)&#xD;
&#xD;
          -  Tetracycline allergy or intolerance&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dan Liang, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Zhongsh Ophthalmic Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Dan Liang, MD</last_name>
    <phone>0086-20-87331766</phone>
    <email>linml0754@gmail.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Zhongshan Ophthalmic Center</name>
      <address>
        <city>Guangzhou</city>
        <state>Guangdong</state>
        <zip>510060</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dan Liang, MD</last_name>
      <phone>0086-20-87331766</phone>
      <email>liangd2@mail.sysu.edu.cn</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>July 28, 2014</study_first_submitted>
  <study_first_submitted_qc>July 28, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 30, 2014</study_first_posted>
  <last_update_submitted>November 16, 2021</last_update_submitted>
  <last_update_submitted_qc>November 16, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 17, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Sun Yat-sen University</investigator_affiliation>
    <investigator_full_name>Dan Liang</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <keyword>Graves' orbitopathy</keyword>
  <keyword>Graves´ ophthalmopathy</keyword>
  <keyword>Thyroid eye disease</keyword>
  <keyword>Thyroid-associated ophthalmopathy</keyword>
  <keyword>Doxycycline</keyword>
  <keyword>EUGOGO</keyword>
  <keyword>CAS</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Eye Diseases</mesh_term>
    <mesh_term>Graves Disease</mesh_term>
    <mesh_term>Graves Ophthalmopathy</mesh_term>
    <mesh_term>Eye Diseases, Hereditary</mesh_term>
    <mesh_term>Genetic Diseases, Inborn</mesh_term>
    <mesh_term>Thyroid Diseases</mesh_term>
    <mesh_term>Endocrine System Diseases</mesh_term>
    <mesh_term>Hyperthyroidism</mesh_term>
    <mesh_term>Autoimmune Diseases</mesh_term>
    <mesh_term>Immune System Diseases</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Doxycycline</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02203682
org study id: 2013MEKY033
nct id: NCT02203682
lead sponsor: 
has dmc: Yes
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).
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: the rate of improvement
time frame: 12 weeks
description: 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%.
measure: Clinical Activity Score (CAS)
time frame: 4weeks and 12 weeks
description: 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.
measure: Proptosis measured by Hertel instrument
time frame: 4weeks and 12 weeks
description: 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.
measure: Eyelid aperture
time frame: 4weeks and 12 weeks
description: 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.
measure: Lid retraction
time frame: 4weeks and 12 weeks
description: 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.
measure: Lid lag
time frame: 4weeks and 12 weeks
description: 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.
measure: Eye motility
time frame: 4weeks and 12 weeks
description: 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.
measure: Graves' Ophthalmopathy Quality of Life Scale
time frame: 4weeks and 12 weeks
description: 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.
measure: C-OSDI
time frame: 4weeks and 12 weeks
description: 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.
measure: the category of adverse events and the frequency of the occurrence of adverse events
time frame: 4weeks and 12 weeks
description: The category of adverse events and the frequency of the occurrence of adverse events are listed to describe the safety.
arm group label: Doxycycline
arm group type: Experimental
description: Tablets Doxycycline 50 mg PO per day for 12 weeks
arm group label: Placebo
arm group type: Placebo Comparator
description: Tablet placebo for 12 weeks
intervention type: Drug
intervention name: Doxycycline hyclate
description: Tab. Doxycycline 50 mg PO per day for 12 weeks
arm group label: Doxycycline
intervention type: Drug
intervention name: Placebo
description: Tablet placebo for 12 weeks
arm group label: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Dan Liang, MD
role: Principal Investigator
affiliation: Zhongsh Ophthalmic Center
last name: Dan Liang, MD
phone: 0086-20-87331766
email: linml0754@gmail.com
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Sun Yat-sen University
investigator full name: Dan Liang
investigator title: MD
mesh term: Eye Diseases
mesh term: Graves Disease
mesh term: Graves Ophthalmopathy
mesh term: Eye Diseases, Hereditary
mesh term: Genetic Diseases, Inborn
mesh term: Thyroid Diseases
mesh term: Endocrine System Diseases
mesh term: Hyperthyroidism
mesh term: Autoimmune Diseases
mesh term: Immune System Diseases
mesh term: Doxycycline