Evaluation of Effect of Doxycycline Verses Placebo on Retinal Function and Diabetic Retinopathy (POC2)

Proof-of-Concept 2 (POC2): Evaluation of Effect of Doxycycline Verses Placebo on Retinal Function and Diabetic Retinopathy Progression in Patients With Mild to Moderate Non-Proliferative Diabetic Retinopathy

This 24 month randomized research study will evaluate whether doxycycline can slow the deterioration or improve retinal function among patients with mild to moderate non-proliferative diabetic retinopathy.

Study Overview

• Status: Completed
• Conditions: Diabetic Retinopathy
• Intervention / Treatment: Drug: doxycycline monohydrate; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Cellulose Placebo Capsule
Experimental: doxycycline monohydrate	Drug: doxycycline monohydrate; 50 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The Mean Change in the Foveal Sensitivity of Matrix Frequency Doubling Perimetry (FDP) From Baseline in the Treated Group Compared to the Placebo Group	Baseline and 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change Thickness Thickness	Anatomic outcomes were assessed through optical coherence. Positive numbers indicate increases in thickness.	Baseline and 24 months
Change in Macular Volume		Baseline and 24 months
Number of Participants With Progression to PDR, and Single or Multiple Step Progression in ETDRS Diabetic Retinopathy Severity Level	Participants are shown categorically by whether they reached PDR, or whether their diabetic retinopathy levels changed by one grade or more, as analyzed by fundus photography.	Baseline to 24 months
Number of Participants Who Developed Vitreous or Preretinal Hemorrhage	Any participants who developed vitreous or preretinal hemorrhage were counted. Had there been any preretinal hemorrhages (a subcategory of vitreous hemorrhage) these would have been shown as a separate row.	24 months

Collaborators and Investigators

• Sponsor: Thomas Gardner
• Collaborators: Juvenile Diabetes Research Foundation; Penn State University
• Investigators: Study Director: Thomas W Gardner, MD.,MS., University of Michigan, Kellogg Eye Center

Publications and helpful links

General Publications

• Scott IU, Jackson GR, Quillen DA, Klein R, Liao J, Gardner TW. Effect of doxycycline vs placebo on retinal function and diabetic retinopathy progression in mild to moderate nonproliferative diabetic retinopathy: a randomized proof-of-concept clinical trial. JAMA Ophthalmol. 2014 Sep;132(9):1137-42. doi: 10.1001/jamaophthalmol.2014.1422.

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): July 1, 2012
• Study Completion (Actual): July 1, 2012

Study Registration Dates

• First Submitted: June 1, 2009
• First Submitted That Met QC Criteria: June 9, 2009
• First Posted (Estimate): June 10, 2009

Study Record Updates

• Last Update Posted (Actual): November 30, 2018
• Last Update Submitted That Met QC Criteria: October 30, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: diabetes; diabetic retinopathy; diabetic eye studies
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Eye Diseases; Endocrine System Diseases; Diabetic Angiopathies; Diabetes Complications; Diabetes Mellitus; Retinal Diseases; Diabetic Retinopathy; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Doxycycline
• Other Study ID Numbers: 30791