Evaluation of Effect of Doxycycline Verses Placebo on Retinal Function and Diabetic Retinopathy

The objective of this proof-of-concept study is to investigate whether doxycycline can slow
the deterioration or improve retinal function among patients with mild to moderate NPDR (with
abnormal retinal function defined as a foveal sensitivity < 30.91 dB on Matrix frequency
doubling perimetry [FDP]). Based on results of the END DR Study, the primary visual function
endpoint in the POC 2 Study will be performance on the Matrix Frequency Doubling Technology
Perimeter. This test was the most sensitive to NPDR of the visual function endpoints the
investigators evaluated in the END DR Study. This selection is aggressive because the
investigators lack natural history data to estimate the 2-year rate of change in the
endpoint; in fact, a major output of this POC 2 Study will be 2-year natural history data
using several visual function endpoints. The investigators are enrolling patients who have
moderate dysfunction; that is, patients who fall outside the 95% confidence interval of
normal performance on FDP. These patients will have the opportunity to improve their FDP
performance to "normal" levels as well as progress to more severe FDP impairment associated
with more advanced disease. Secondary endpoints include visual acuity, contrast sensitivity,
visual field, and dark adaptation. The tests will be performed in the Ophthalmology
Department of the Penn State College of Medicine. 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 mild to moderate NPDR (ETDRS levels 20 to
43), and in whom retinal photocoagulation is not anticipated (by the investigator) within the
subsequent 2 years. Participants will be randomized to receive either doxycycline monohydrate
50mg or an identical placebo once daily for 24 months.

Inclusion Criteria:

- age ≥ 18 years old

- diagnosis of type 1 or type 2 diabetes mellitus (defined as current regular use of
oral anti-hyperglycemia agents and/or insulin for the treatment of diabetes)

- have a hemoglobin A1c < 11% at pre-qualification visit

- able and willing to give informed consent

- best-corrected ETDRS visual acuity (10) in study eye ≥ 69 letters (20/40)

- mild to moderate non-proliferative diabetic retinopathy (ETDRS levels 20 to 43) (11),
and in whom retinal photocoagulation is not anticipated (by the investigator) within
the subsequent 2 years

- able to perform reliable visual field and dark adaptation testing

- central subfield thickness on OCT ≤ 275 microns

- media clarity and pupil dilation sufficient for high-quality fundus photographs

- abnormal retinal function defined as:

- abnormal FDP function as defined by a foveal sensitivity ≤ 30.91 dB

Exclusion Criteria:

- prior panretinal photocoagulation in the study eye

- prior focal/grid laser photocoagulation in the macula in the study eye

- intraocular pressure in the study eye > 22 mmHg by Goldmann tonometry

- history of pars plana vitrectomy 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 24months

- 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