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.

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 mild or moderate proliferative diabetic retinopathy (retinal and /or optic disk neovascularization less than the "high-risk" ETDRS level 61 or 65), neovascularization of the disc or neovascularization elsewhere >1/2 disc area 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
• history of headaches associated with tetracycline therapy
• history of pseudotumor cerebri
• pregnancy; for women of child-bearing potential, a serum 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. cellulose, 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
• patients taking strontium, acitretin or tretinoin will be excluded due to the potential for serious drug interactions with doxycycline
• patients with abnormal ALT or AST at baseline will be referred to their primary care physician for medical clearance for participation in this study

• Drug: doxycycline monohydrate
• Drug: placebo

• Experimental: stratified equally to doxycycline monohydrate 50mg taken once daily for 24 months
• Placebo Comparator: stratified equally to placebo taken once daily for 24 months

Inclusion Criteria:

• age ≥ 18 years
• diagnosis of type 1 or type 2 diabetes mellitus
• have a hemoglobin A1c between 7% and 11% at pre-qualification visit
• 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) or retinal and/or optic disk neovascularization less than the "high-risk" characteristics defined by the Diabetic Retinopathy Study (ETDRS level61- 65), 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 in the study eye
• 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
• 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 in the opinion of the investigator
• 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.