Prednisone Versus Doxycycline in the Treatment of Graves' Orbitopathy

Study Description

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Brief Summary:

The aim of this study is to compare the efficacy and safety of prednisone versus sub-antimicrobial dose doxycycline (50 mg/d) in the treatment of active moderate-severe Graves' Orbitopathy (GO).

Condition or disease	Intervention/treatment	Phase
Thyroid Associated Opthalmopathies	Drug: Prednisone+placebo of Doxycycline; Drug: Doxycycline+placebo of Prednisone	Phase 2; Phase 3

Detailed Description:

Graves' orbitopathy is an autoimmune disease characterized by an inflammatory phase followed by fibrosis. Surgery to correct eyelid swelling, proptosis, and diplopia is effective, but can not be done until the inflammatory phase has passed. To arrest the inflammatory phase, several types of immunosuppressive treatments have been investigated. Corticosteroids are the first-choice immunosuppressive treatment, having a successful outcome of 50-70% in patients. However, long time usage of corticosteroids often cause severe side-effects.

Sub-antimicrobial dose doxycycline posses known anti-inflammatory effects that are separate from their antibacterial mode of action. This mode of action has lead to the routine use of sub-antimicrobial dose doxycycline for treating inflammatory or autoimmune diseases, such as rosacea, periodontitis and multiple sclerosis. The mechanism is by inhibiting lymphocyte proliferation and production of colony-stimulating factor, inflammatory cytokines, and immunoglobulins, factors thought to play a role in the orbital autoimmune process. These mechanisms make them, in theory, an attractive option of doxycycline for treating Graves' Orbitopathy. In addition, only few adverse events were reported when doxycycline were administered for 3 months in patients with periodontitis or rosacea.

We propose to compare the effect and safety of sub-antimicrobial dose doxycycline versus prednisone for treating non-sight threatening, moderate-severe, inflammatory GO.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	146 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	The Effect of Prednisone Versus Doxycycline in Active, Moderately Severe Graves' Orbitopathy: A Randomized, Multi-center, Double-blind, Parallel-controlled Trial
Study Start Date :	November 2012
Estimated Primary Completion Date :	January 2016
Estimated Study Completion Date :	January 2016

Arms and Interventions

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Arm	Intervention/treatment
Active Comparator: Prednisone+placebo of Doxycycline; Prednisone: 50 mg/d for 14 day, tailed by 40 mg/d for 14 day, 30 mg/d for 28 day, 20 mg/d for 28 day, 15 mg/d for 14 day, 10 mg/d for 14 day, in total 16 weeks; Placebo of doxycycline: administered for 16 weeks.	Drug: Prednisone+placebo of Doxycycline; Prednisone: 50 mg/d for 14 day, tailed by 40 mg/d for 14 day, 30 mg/d for 28 day, 20 mg/d for 28 day, 15 mg/d for 14 day, 10 mg/d for 14 day, in total 16 weeks; Placebo of doxycycline: administered for 16 weeks; Other Name: deltacortisone
Experimental: Doxycycline+placebo of Prednisone; Doxycycline: 50 mg/d for 12 weeks, and placebo for another 4 weeks; Placebo of prednisone: administered for 16 weeks.	Drug: Doxycycline+placebo of Prednisone; Doxycycline: 50 mg PO per day for 12 weeks, and placebo for another 4 weeks; Placebo of prednisone: administered for 16 weeks.; Other Names: Dolotard; Tibirox; Biomycin

Outcome Measures

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Primary Outcome Measures :

1. Overall treatment response [ Time Frame: 24 weeks ]

   Overall treatment response was graded as: improvement, deterioration, and no success.

   1. Improvement, when at least one major criteria or two minor criteria were achieved, in absence of deterioration of any criterion in that observed eye.Three major criteria were: improvement in diplopia grade (disappearance or change in grade); improvement of ≥8 degrees in any direction of eye movements; reduction of three points or more in CAS. Four minor criteria were: reduction of 2 mm or more in eyelid aperture; reduction of 2 mm or more in proptosis; improvement in grade of soft tissue swelling; decrease in CAS by at least two points.
   2. Deterioration, defined as occurrence of DON, and/or worsening of soft tissue swelling, and/or worsening of diplopia, and/or an increase of ≥2 mm in lid aperture, and/or an increase of ≥2 mm in proptosis, and/or a decrease of ≥8 degrees in duction.
   3. No success was defined if there was no change or the changes did not reach the improvement criteria.

Secondary Outcome Measures :

1. • Health related quality of life questionnaires (GO-QoL) [ Time Frame: 24 weeks ]
2. • Safety and tolerability as assessed by adverse events, vital signs [ Time Frame: 48 weeks ]
3. • Quantitative changes of rectus diameter measured by MRI scan [ Time Frame: 24 weeks ]
4. Relapse [ Time Frame: 48 weeks ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 60 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Confirmed diagnosis of Graves' Orbitopathy (as defined by Bartley and Gorman)

  • Eyelid retraction (upper eyelid margin at or above the superior corneoscleral limbus in primary gaze without frontalis muscle contraction) in association with any one of the following:

    • Thyroid dysfunction or abnormal regulation (increased serum thyroxine or triiodothyronine level, decreased serum thyroid stimulating hormone level, absence of thyroid radioiodine uptake suppression after administration of triiodothyronine, or the presence of thyroid stimulating immunoglobulins in serum)
    • Exophthalmos
    • Extraocular muscle involvement (restrictive myopathy or objective evidence of enlarged muscles)
    • Optic nerve dysfunction (abnormal visual acuity, color vision, pupillary reaction or perimetry not attributable to other causes) OR

  • Thyroid dysfunction or abnormal regulation in association with any one of the following:

    • Exophthalmos
    • Extraocular muscle involvement
    • Optic nerve dysfunction
• Moderate-severe GO According to EUGOGO statement, patients with moderate-severe GO usually have any one or more of the following：lid retraction≥2mm, moderate or severe soft tissue involvement, exophthalmos≥3mm above normal for race and gender, inconstant, or constant diplopia.
• Clinical activity score ≥ 3
• Being euthyroid for at least 1 months before the date of inclusion
• Must be able to swallow tablets
• Written informed consent is obtained

Exclusion Criteria:

• Mild Graves' Orbitopathy
• Sight-threatening Graves' Orbitopathy
• Clinical activity score ＜ 3
• Previous treatment for GO Oral steroids, intravenous steroids, radiotherapy
• Pregnant females as determined by positive (serum or urine) human chorionic gonadotrophin (hCG) test at screening or prior to dosing, or lactating females
• Uncontrolled diabetes or hypertension
• History of mental / psychiatric disorder
• Hepatic dysfunction (Albumin (Alb) , Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) and Alkaline phosphates levels must be within normal range for eligibility)
• Renal impairment (Urea and Creatinine levels must be within normal range)
• Doxycycline or Prednisone allergy or intolerance

Contacts and Locations

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Contacts

Contact: Dan Liang, MD	0086-20-87331766	liangd2@mail.sysu.edu.cn
Contact: Miaoli Lin, md	0086-20-87331537	linml0754@gmail.com

Locations

China, Beijing
Peking Union Medical College Hospital	Recruiting
Beijing, Beijing, China, 100730
Contact: Yong Zhong, MD +86-10-69156114 yzhong_eye@yahoo.com.cn
China, Guangdong
Zhongshan Ophthalmic Center	Recruiting
Guangzhou, Guangdong, China, 510060
Contact: Dan Liang, MD 0086-20-87331766 liangd2@mail.sysu.edu.cn
JOINT SHANTOU INTERNATIONALL EYE CENTER of Shantou University and the Chinese University of Hong Kong	Recruiting
Shantou, Guangdong, China, 515041
Contact: Mingzhi Zhang, MD +86-754-88393501 zmz@jsiec.org
Shenzhen Eye Hospital	Recruiting
Shenzhen, Guangdong, China, 518040
Contact: Guiqin Liu, MD +86-755-23959600 liuguiqin9@yahoo.com.cn
China, Henan
Henan Eye Institue, Henan, China	Recruiting
Zhengzhou, Henan, China, 450003
Contact: Liya wang, MD 0086-13937169191 wangliya55@126.com
China, Hunan
The second xiangya hospital of central south university	Recruiting
Changsha, Hunan, China, 410011
Contact: Wei Xiong, MD 0086-138-0846-9035 weixiong420@163.com

Sponsors and Collaborators

Sun Yat-sen University

Investigators

Study Chair:	Dan Liang, MD	Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
Principal Investigator:	Liya Wang, MD	Henan Eye Institue, Henan, China
Principal Investigator:	Luosheng Tang, MD	The second xiangya hospital of central south university, Hunan, China

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

Genetics Home Reference related topics: Lenz microphthalmia syndrome oculofacioc 

MedlinePlus related topics: Antibiotics Eye Diseases Thyroid Diseases 

U.S. FDA Resources 

Responsible Party:	Dan Liang, Zhongshan Ophthalmic Center, Sun Yat-sen University
ClinicalTrials.gov Identifier:	NCT01809444 History of Changes
Other Study ID Numbers:	5010-doxy
First Posted:	March 12, 2013
Last Update Posted:	December 10, 2013
Last Verified:	December 2013

Additional relevant MeSH terms:

Graves Ophthalmopathy; Graves Disease; Eye Diseases, Hereditary; Eye Diseases; Exophthalmos; Orbital Diseases; Goiter; Thyroid Diseases; Endocrine System Diseases; Hyperthyroidism; Autoimmune Diseases; Immune System Diseases; Prednisone	Doxycycline; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Anti-Bacterial Agents; Anti-Infective Agents; Antimalarials; Antiprotozoal Agents; Antiparasitic Agents