Prednisone Versus Doxycycline in the Treatment of Graves' Orbitopathy

The Effect of Prednisone Versus Doxycycline in Active, Moderately Severe Graves' Orbitopathy: A Randomized, Multi-center, Double-blind, Parallel-controlled Trial

Sponsors

Lead Sponsor: Sun Yat-sen University

Source Sun Yat-sen University
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.

Overall Status Unknown status
Start Date November 2012
Completion Date January 2016
Primary Completion Date January 2016
Phase Phase 2/Phase 3
Study Type Interventional
Primary Outcome
Measure Time Frame
Overall treatment response 24 weeks
Secondary Outcome
Measure Time Frame
• Health related quality of life questionnaires (GO-QoL) 24 weeks
• Safety and tolerability as assessed by adverse events, vital signs 48 weeks
• Quantitative changes of rectus diameter measured by MRI scan 24 weeks
Relapse 48 weeks
Enrollment 146
Condition
Intervention

Intervention Type: Drug

Intervention Name: Prednisone+placebo of Doxycycline

Description: 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

Arm Group Label: Prednisone+placebo of Doxycycline

Other Name: deltacortisone

Intervention Type: Drug

Intervention Name: Doxycycline+placebo of Prednisone

Description: Doxycycline: 50 mg PO per day for 12 weeks, and placebo for another 4 weeks; Placebo of prednisone: administered for 16 weeks.

Arm Group Label: Doxycycline+placebo of Prednisone

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

Gender: All

Minimum Age: 18 Years

Maximum Age: 60 Years

Healthy Volunteers: No

Overall Official
Overall Contact

Last Name: Dan Liang, MD

Phone: 0086-20-87331766

Email: [email protected]

Location
Facility: Status: Contact:
Peking Union Medical College Hospital | Beijing, Beijing, 100730, China Recruiting Yong Zhong, MD +86-10-69156114 [email protected]
Zhongshan Ophthalmic Center | Guangzhou, Guangdong, 510060, China Recruiting Dan Liang, MD 0086-20-87331766 [email protected]
JOINT SHANTOU INTERNATIONALL EYE CENTER of Shantou University and the Chinese University of Hong Kong | Shantou, Guangdong, 515041, China Recruiting Mingzhi Zhang, MD +86-754-88393501 [email protected]
Shenzhen Eye Hospital | Shenzhen, Guangdong, 518040, China Recruiting Guiqin Liu, MD +86-755-23959600 [email protected]
Henan Eye Institue, Henan, China | Zhengzhou, Henan, 450003, China Recruiting Liya wang, MD 0086-13937169191 [email protected]
The second xiangya hospital of central south university | Changsha, Hunan, 410011, China Recruiting Wei Xiong, MD 0086-138-0846-9035 [email protected]
Location Countries

China

Verification Date

December 2013

Responsible Party

Type: Principal Investigator

Investigator Affiliation: Sun Yat-sen University

Investigator Full Name: Dan Liang

Investigator Title: Zhongshan Ophthalmic Center

Has Expanded Access No
Condition Browse
Number Of Arms 2
Arm Group

Label: Prednisone+placebo of Doxycycline

Type: Active Comparator

Description: 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.

Label: Doxycycline+placebo of Prednisone

Type: Experimental

Description: Doxycycline: 50 mg/d for 12 weeks, and placebo for another 4 weeks; Placebo of prednisone: administered for 16 weeks.

Study Design Info

Allocation: Randomized

Intervention Model: Parallel Assignment

Primary Purpose: Treatment

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Source: ClinicalTrials.gov