Effect of Doxycycline vs Placebo on Retinal Function and Diabetic Retinopathy Progression in Patients With Severe Nonproliferative or Non–High-Risk Proliferative Diabetic Retinopathy

Abstract

may contribute to the pathogenesis of diabetic retinopathy (DR). OBJECTIVES To investigate, in a proof-of-concept clinical trial, whether low-dose oral doxycycline monohydrate can (1) slow the deterioration of, or improve, retinal function or (2) induce regression or slow the progression of DR in patients with severe nonproliferative DR (NPDR) or non-high-risk proliferative (PDR), and to determine the potential usefulness of visual function end points to expedite the feasibility of conducting proof-of-concept clinical trials in patients with DR. DESIGN, SETTING, AND PARTICIPANTS We conducted a randomized, double-masked, 24-month proof-of-concept clinical trial. Thirty patients (from hospital-based retina practices) with 1 or more eyes with severe NPDR or PDR less than Early Treatment Diabetic Retinopathy Study-defined high-risk PDR. INTERVENTIONS Patients were randomized to receive 50 mg of doxycycline monohydrate or placebo daily for 24 months. MAIN OUTCOMES AND MEASURES Change at 24 months compared with baseline in functional factors (frequency doubling perimetry [FDP], Humphrey photopic Swedish Interactive Thresholding Algorithm 24-2 testing, contrast sensitivity, dark adaptation, visual acuity, and quality of life) and anatomic factors (Early Treatment Diabetic Retinopathy Study DR severity level, area of retinal thickening, central macular thickness, macular volume, and retinal vessel diameters). RESULTS From baseline to month 24, mean FDP foveal sensitivity decreased in the placebo group (−1.9 dB) and increased in the doxycycline group (+1.8 dB) (P = .02). A higher mean FDP foveal sensitivity in the doxycycline group compared with the placebo group was detected at 6 months (P = .04), and this significant difference persisted at 12 and 24 months. A difference between the groups was not detected with respect to the other visual function outcomes and all anatomic outcomes assessed. CONCLUSIONS AND RELEVANCE To our knowledge, this is the first observation suggesting a link between a low-dose oral anti-inflammatory agent and subclinical improvement in inner retinal function. Oral doxycycline may be a promising therapeutic strategy targeting the inflammatory component of DR. Furthermore, study results suggest that FDP, which primarily measures inner retinal function, is responsive to intervention and may be a useful clinical trial end point for proof-of-concept studies in patients with DR. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00511875

Glucose variability and inner retinal sensory neuropathy in persons with type 1 diabetes mellitus

“…Indeed, Scott et al 30 recently used FDP as a clinical trial end point to evaluate the efficacy of doxycycline in preserving retinal sensitivity during diabetes. They found that doxycycline treatment was associated with improved FDP sensitivity at the end of the 24-month trial, although further work is needed to understand the clinical significance of improvements in FDP sensitivity.…”

New Therapeutic Approaches in Diabetic Retinopathy

“…The 2-year results showed that foveal sensitivity (measured by photopic visual field) decreased among the placebo group, while it increased in the group receiving doxycycline, when compared with baseline. However, all other anatomical and functional outcomes were not significantly different between the two groups [94].…”

Contribution of microglia‐mediated neuroinflammation to retinal degenerative diseases

“…In a pilot proofof-concept study (single-center, prospective, and open-label phase I/II clinical trial) with patients with diabetic macular edema, the treatment with minocycline improved visual function, central macular edema, and vascular leakage [224]. In a randomized, double-masked clinical trial in patients with severe nonproliferative diabetic retinopathy or nonhigh-risk proliferative diabetic retinopathy, doxycycline, a semisynthetic second-generation tetracycline also with antiinflammatory properties, improved foveal frequency doubling perimetry, suggesting a link between a low-dose of this oral anti-inflammatory agent and subclinical improvement in inner retinal function [225].…”