Diabetic Retinopathy
Conditions
Keywords
diabetic retinopathy, diabetes, diabetic eye studies
Brief summary
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.
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.
Interventions
50 mg
DRUGPlacebo
Cellulose Placebo Capsule
Sponsors
Penn State University
Juvenile Diabetes Research Foundation
Thomas Gardner
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| 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
| Measure | Time frame | Description |
|---|---|---|
| Change Thickness Thickness | Baseline and 24 months | Anatomic outcomes were assessed through optical coherence. Positive numbers indicate increases in thickness. |
| 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 | Baseline to 24 months | 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. |
| Number of Participants Who Developed Vitreous or Preretinal Hemorrhage | 24 months | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo
Placebo: Cellulose Placebo Capsule | 17 |
| Doxycycline Monohydrate doxycycline monohydrate: 50 mg | 16 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Doxycycline Monohydrate |
|---|---|---|---|
| Age, Continuous | 56.76 years STANDARD_DEVIATION 7.61 | 57.57 years STANDARD_DEVIATION 10.41 | 58.44 years STANDARD_DEVIATION 12.96 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 32 Participants | 15 Participants |
| Region of Enrollment United States | 17 participants | 33 participants | 16 participants |
| Sex: Female, Male Female | 5 Participants | 12 Participants | 7 Participants |
| Sex: Female, Male Male | 12 Participants | 21 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 16 |
| other Total, other adverse events | 16 / 17 | 14 / 16 |
| serious Total, serious adverse events | 4 / 17 | 8 / 16 |
Outcome results
Primary
The Mean Change in the Foveal Sensitivity of Matrix Frequency Doubling Perimetry (FDP) From Baseline in the Treated Group Compared to the Placebo Group
Time frame: Baseline and 24 months
Population: Two participants in the placebo group and one in the doxycycline group were unavailable for 24 month results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Mean Change in the Foveal Sensitivity of Matrix Frequency Doubling Perimetry (FDP) From Baseline in the Treated Group Compared to the Placebo Group | 2.80 dB | Standard Deviation 3.8 |
| Doxycycline Monohydrate | The Mean Change in the Foveal Sensitivity of Matrix Frequency Doubling Perimetry (FDP) From Baseline in the Treated Group Compared to the Placebo Group | 0.13 dB | Standard Deviation 4.45 |
Secondary
Change in Macular Volume
Time frame: Baseline and 24 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Macular Volume | 0.06 mm^3 | Standard Deviation 0.34 |
| Doxycycline Monohydrate | Change in Macular Volume | 0.23 mm^3 | Standard Deviation 0.67 |
Secondary
Change Thickness Thickness
Anatomic outcomes were assessed through optical coherence. Positive numbers indicate increases in thickness.
Time frame: Baseline and 24 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change Thickness Thickness | Central subfield thickness | 17.5 µm | Standard Deviation 27.3 |
| Placebo | Change Thickness Thickness | Center point thickness | 25.6 µm | Standard Deviation 41.7 |
| Doxycycline Monohydrate | Change Thickness Thickness | Central subfield thickness | 21.3 µm | Standard Deviation 72.5 |
| Doxycycline Monohydrate | Change Thickness Thickness | Center point thickness | 26.1 µm | Standard Deviation 81.1 |
Secondary
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.
Time frame: 24 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants Who Developed Vitreous or Preretinal Hemorrhage | 0 Participants |
| Doxycycline Monohydrate | Number of Participants Who Developed Vitreous or Preretinal Hemorrhage | 0 Participants |
Secondary
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.
Time frame: Baseline to 24 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Progression to PDR, and Single or Multiple Step Progression in ETDRS Diabetic Retinopathy Severity Level | Progressed to PDR | 0 Participants |
| Placebo | Number of Participants With Progression to PDR, and Single or Multiple Step Progression in ETDRS Diabetic Retinopathy Severity Level | >=1 severity level ETDRS | 9 Participants |
| Placebo | Number of Participants With Progression to PDR, and Single or Multiple Step Progression in ETDRS Diabetic Retinopathy Severity Level | >=2 severity level ETDRS | 0 Participants |
| Placebo | Number of Participants With Progression to PDR, and Single or Multiple Step Progression in ETDRS Diabetic Retinopathy Severity Level | >=3 severity level ETDRS | 0 Participants |
| Doxycycline Monohydrate | Number of Participants With Progression to PDR, and Single or Multiple Step Progression in ETDRS Diabetic Retinopathy Severity Level | >=3 severity level ETDRS | 1 Participants |
| Doxycycline Monohydrate | Number of Participants With Progression to PDR, and Single or Multiple Step Progression in ETDRS Diabetic Retinopathy Severity Level | Progressed to PDR | 1 Participants |
| Doxycycline Monohydrate | Number of Participants With Progression to PDR, and Single or Multiple Step Progression in ETDRS Diabetic Retinopathy Severity Level | >=2 severity level ETDRS | 2 Participants |
| Doxycycline Monohydrate | Number of Participants With Progression to PDR, and Single or Multiple Step Progression in ETDRS Diabetic Retinopathy Severity Level | >=1 severity level ETDRS | 7 Participants |