Clinical trial NCT01809444: Prednisone Versus Doxycycline in the Treatment of Graves' Orbitopathy
Official title: The Effect of Prednisone Versus Doxycycline in Active, Moderately Severe Graves' Orbitopathy: A Randomized, Multi-center, Double-blind, Parallel-controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
PHASE3
Conditions: Thyroid Associated Opthalmopathies
Lead sponsor: Sun Yat-sen University
Sponsor class: OTHER
First posted: 2013-03-12
Enrollment: 146
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

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.

Eligibility 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

Primary outcomes:
measure: Overall treatment response
timeFrame: 24 weeks
Secondary outcomes:
measure: • Health related quality of life questionnaires (GO-QoL)
timeFrame: 24 weeks
measure: • Safety and tolerability as assessed by adverse events, vital signs
timeFrame: 48 weeks
measure: • Quantitative changes of rectus diameter measured by MRI scan
timeFrame: 24 weeks
measure: Relapse
timeFrame: 48 weeks
Other outcomes:
Locations:
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
city: Guangzhou
country: China
facility: Zhongshan Ophthalmic Center
state: Guangdong
city: Shantou
country: China
facility: JOINT SHANTOU INTERNATIONALL EYE CENTER of Shantou University and the Chinese University of Hong Kong
state: Guangdong
city: Shenzhen
country: China
facility: Shenzhen Eye Hospital
state: Guangdong
city: Zhengzhou
country: China
facility: Henan Eye Institue, Henan, China
state: Henan
city: Changsha
country: China
facility: The second xiangya hospital of central south university
state: Hunan
Study officials:
affiliation: Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China
name: Dan Liang, MD
role: STUDY_CHAIR
affiliation: Henan Eye Institue, Henan, China
name: Liya Wang, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: The second xiangya hospital of central south university, Hunan, China
name: Luosheng Tang, MD
role: PRINCIPAL_INVESTIGATOR
References: