Official Title: “Evaluation of Effect of Doxycyline Verses Placebo on Retinal Function and Posterior Segment Neovascularization in Patients With Severe Non-Proliferative or Early (Non-High-Risk) Proliferative Diabetic Retinopathy”

This 24 month randomized research study will evaluate whether doxycycline can 1) slow the deterioration or improve retinal function and/or 2) induce regression, or slow progression, of diabetic retinopathy in participants over 18 years of age with type 1 or type 2 diabetes with severe non-proliferative or early proliferative diabetic retinopathy.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: April 2011

The objectives of this proof-of-concept study are to investigate whether doxycycline can 1) slow the deterioration or improve retinal function and/or 2) induce regression, or slow progression, of diabetic retinopathy. The tests will be performed in the Ophthalmology Departments of the Penn State College of Medicine and Glostrup Hospital, Copenhagen, Denmark.

The 24 month proof-of-concept clinical study will involve a prospective, randomized, double-masked clinical trial including 60 adult patients with type 1 or type 2 diabetes who have severe non-proliferative diabetic retinopathy (ETDRS level 53E) or retinal and/or optic disk neovascularization >1/2 disc area and less than the "high-risk" characteristics defined by the Diabetic Retinopathy Study (17) (ETDRS level 65), and in whom panretinal photocoagulation is not imminently required in the ophthalmologist's judgment.

Systemic Exclusion Criteria: - unstable medical status (e.g. glycemic control, blood pressure, cardiovascular disease) in the opinion of investigator - significant renal disease (defined as a serum creatinine > 2.5 mg/dL), - systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg - pregnancy; for women of child-bearing potential, a urine pregnancy test will be performed. - lactating or intending to become pregnant during the study period (at least 24 months) - sexually active women of child-bearing potential not actively practicing birth control by using a medically accepted device or therapy (that is, intrauterine device, hormonal contraceptive, or barrier devices) during the study period (at least 24 months); since doxycycline may interfere with the effectiveness of hormonal contraceptives, sexually active women of child-bearing potential who use a hormonal contraceptive will be required to use a second form of contraception to safeguard against contraceptive failure while participating in the study - known allergy/intolerance to doxycycline or any ingredient in the study drug or placebo (e.g. hypromellose, iron oxide, methacrylic acid copolymer, polyethylene glycol, polysorbate 80, sugar spheres, talc, titanium dioxide, and triethyl citrate) - patients taking phenytoin, barbiturates or carbamazepine, with gastroparesis, with a history of gastrectomy, gastric bypass surgery or otherwise deemed achlorhydric or with a BMI > 30 kg/m2 will also be excluded because of altered doxycycline pharmacokinetics and/or bioavailability

Intervention(s) in this Clinical Trial

• Drug: doxycycline monohydrate
  • 50mg once daily for 24 months

Arms, Groups and Cohorts in this Clinical Trial

• Placebo Comparator: A
  • stratified equally to either doxycycline monohydrate 40mg or placebo taken once daily for 24 months

Primary Measures

• dark adaptation, scotopic visual fields, photopic visual fields, frequency doubling perimetry, ETDRS visual acuity, development or increase of neovascularization, need for panretinal photocoagulation, development of vitreous or preretinal hemorrhage
  • Time Frame: Over the study period
    Safety Issue?: No

Secondary Measures

• area of retinal thickening, central subfield thickness, macular volume, central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE), arteriovenous ratio (AVR = CRAE/CRVE)
  • Time Frame: Over the study period
    Safety Issue?: No

Inclusion Criteria:

• age ≥ 18 years
• diagnosis of type 1 or type 2 diabetes mellitus
• able and willing to give informed consent
• best-corrected ETDRS visual acuity in study eye ≥ 49 letters (20/100)
• severe non-proliferative diabetic retinopathy (ETDRS level 53E) (19) or retinal and/or optic disk neovascularization >1/2 disc area and less than the "high-risk" characteristics defined by the Diabetic Retinopathy Study (ETDRS level 65) (17), and in whom panretinal photocoagulation is not imminently required in the ophthalmologist's judgment
• able to perform reliable visual field and dark adaptation testing
• central subfield thickness on OCT of ≤ 275microns
• foveal fixation present in each eye (assessed by fundus photography using an internal fixation pointer or assessed by the investigator)
• media clarity and pupil dilation sufficient for high-quality fundus photographs and fluorescein angiograms

Exclusion Criteria:

• high-risk neovascularization in study eye
• prior panretinal photocoagulation in the study eye
• focal/grid laser photocoagulation in the macula within the past 15 weeks in the study eye
• intraocular pressure > 22mmHg by Goldmann Tonometry
• history of pars plana vitrectomy in the study eye
• vitreous or pre-retinal hemorrhage in the study eye
• systemic or intravitreal anti-VEGF agent to the study eye or the fellow eye within the past 3 months
• peribulbar steroid injection to the study eye or the fellow eye within the past 6 months
• intravitreal triamcinolone acetonide to the study eye within the past 4 months;
• expectation by the investigator that retinal photocoagulation or other treatment for diabetic retinopathy (e.g. focal/grid laser to study eye, intravitreal triamcinolone acetonide to study eye, intravitreal anti-VEGF agent to study or fellow eye, ruboxistaurin or systemic anti-VEGF agent for diabetic macular edema) will be administered in the subsequent 24 months
• best-corrected ETDRS visual acuity < 49 letters (20/100) in the fellow eye
• an ocular condition (other than diabetes) is present in the study eye that, in the opinion of the investigator, might alter visual acuity during the course of the study (e.g. retinal vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, Irvine-Gass Syndrome, etc)
• anticipated need for cataract surgery in the study eye in the subsequent 24 months
• history of major ocular surgery (including cataract surgery, scleral buckle, any intraocular surgery, etc) in the study eye within prior 6 months or anticipated within the subsequent 24 months following randomization
• aphakia in the study eye
• history of YAG capsulotomy performed in the study eye within 2 months prior to randomization.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Penn State University

Overall Clinical Trial Officials and Contacts

Thomas W Gardner, MD MS Study Director Penn State University, Milton S. Hershey Medical Center  

Information obtained from ClinicalTrials.gov on October 15, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00511875

Study ID Number: 25234

ClinicalTrials.gov Identifier: NCT00511875

Health Authority: United States: Food and Drug Administration

Penn State University, Milton S. Hershey Medical Center

Juvenile Diabetes Research Foundation

Penn State Hershey Eye Center, Department of Ophthalmology