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Oral minocycline for the treatment of diabetic macular edema (DME): results of a phase I/II clinical study.

ABSTRACT: Inflammation contributes significantly to the pathogenesis of diabetic macular edema (DME). In particular, retinal microglia demonstrate increased activation and aggregation in areas of DME. Study authors investigated the safety and potential efficacy of oral minocycline, a drug capable of inhibiting microglial activation, in the treatment of DME.A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with fovea-involving DME who received oral minocycline 100 mg twice daily for 6 months. Main outcome measurements included best-corrected visual acuity (BCVA), central retinal subfield thickness (CST), and central macular volume using spectral domain optical coherence tomography (SD-OCT) and late leakage on fluorescein angiography (FA).Findings indicated that the study drug was well tolerated and not associated with significant safety issues. In study eyes, mean BCVA improved continuously from baseline at 1, 2, 4, and 6 months by +1.0, +4.0, +4.0, and +5.8 letters, respectively, while mean retinal thickness (CST) on OCT decreased by -2.9%, -5.7%, -13.9, and -8.1% for the same time points. At month 6, mean area of late leakage on FA decreased by -34.4% in study eyes. Mean changes in contralateral fellow eyes also demonstrated similar trends. Improvements in outcome measures were not correlated with concurrent changes in systemic factors.In this pilot proof-of-concept study of DME, minocycline as primary treatment was associated with improved visual function, central macular edema, and vascular leakage, comparing favorably with historical controls from previous studies. Microglial inhibition with oral minocycline may be a promising therapeutic strategy targeting the inflammatory etiology of DME. (ClinicalTrials.gov number, NCT01120899.).

SUBMITTER: Cukras CA

PROVIDER: S-EPMC3390218 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Oral minocycline for the treatment of diabetic macular edema (DME): results of a phase I/II clinical study.

Cukras Catherine A CA Petrou Philip P Chew Emily Y EY Meyerle Catherine B CB Wong Wai T WT

Investigative ophthalmology & visual science 20120622 7

<h4>Purpose</h4>Inflammation contributes significantly to the pathogenesis of diabetic macular edema (DME). In particular, retinal microglia demonstrate increased activation and aggregation in areas of DME. Study authors investigated the safety and potential efficacy of oral minocycline, a drug capable of inhibiting microglial activation, in the treatment of DME.<h4>Methods</h4>A single-center, prospective, open-label phase I/II clinical trial enrolled five participants with fovea-involving DME ...[more]

PMID: 22589436

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Project description:BACKGROUND:Diabetic macular edema (DME) shows a gradual and sustained functional and morphologic response to anti-vascular endothelial growth factor (VEGF) drugs, but the optimal schedule for initiation of anti-VEGF therapy is not known. This study evaluates the treatment response behavior of DME in the Phase 3 trials of intravitreal aflibercept, with 5 initial intravitreal aflibercept injections (IAI), 2 mg every 4 weeks (2q4), in the upload phase. METHODS:This post hoc pooled analysis of the VISTA-DME (NCT01363440) and VIVID-DME (NCT01331681) trials evaluated the change in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) during the upload phase, using pooled data from both IAI treatment groups [2q4 and 2 mg every 8 weeks (2q8)]. The mean visit-to-visit change in BCVA and CRT, and the respective rate of gainers and losers was calculated for each successive visit. A secondary analysis compared the visit-to-visit change in BCVA between the 2q4 and 2q8 treatment arms during the upload period and the first year treatment period. RESULTS:The majority of eyes showed a continuing improvement of BCVA after the first IAI. The proportions of eyes gaining BCVA (?5 letters) at each visit compared with the previous visit during the IAI 2q4 upload phase were 60 (4-weeks), 19 (8-weeks), 16 (12-weeks), 15 (16-weeks), and 14 % (20-weeks). In contrast, the proportions of eyes losing BCVA (?5 letters) were 3 (4-weeks), 7 (8-weeks), 7 (12-weeks), 9 (16-weeks), and 8 % (20-weeks), respectively. The odds of BCVA (?5 letters) gain/loss exceeded 1.7 at each visit (range 1.7-20). Overall, the proportion of patients with BCVA gain ?5 letters at week 20 (compared with baseline) was 76 and 80 % in the 2q4 and 2q8 groups, respectively. The proportions of eyes showing a visit-to-visit decrease in CRT of ?30 µm during the first 5 IAI were 77 (4-weeks), 27 (8-weeks), 21 (12-weeks), 17 (16-weeks), and 12 % (20-weeks). In the secondary analysis, the BCVA outcomes were similar for the 2q8 and 2q4 treatment arms. CONCLUSIONS:The data presented here are consistent with continual functional and anatomic improvement following the fourth and fifth initial 2q4 injections, suggesting that an intensive and sufficiently long upload may be beneficial. Trial registration VIVID-DME: Clinicaltrials.gov: NCT01331681; VISTA-DME: Clinicaltrials.gov: NCT01363440.

Project description:Our purpose was to compare the impact in diabetic macula edema (DME) of two intravitreal drugs (0.5 mg ranibizumab vs. 8 mg triamcinolone) on changes in retinal morphology in spectral-domain optical coherence tomography (SD OCT) images, color fundus photography (CF) and fluorescein angiography (FA) images during a 1-year follow-up.Post hoc analysis was conducted of morphologic characteristics in OCT, FA and CF images of eyes with a center involving DME that were included in a prospective double-masked randomized trial. Eligible patients were divided at random into two groups receiving either pro re nata treatment with 0.5 mg ranibizumab or 8 mg triamcinolone after a fixed loading dose. OCT and CF images were acquired at monthly visits and FA images every three months.Twenty-five eyes of 25 patients (ranibizumab: n = 10; triamcinolone: n = 15) were included in this study. Patients treated with ranibizumab showed better visual acuity results after 12 months than patients receiving triamcinolone (p = 0.015) although edema reduction was similar (p = 0.426) in both groups. The initial effect on macular edema shedding after a single ranibizumab injection could be amplified with the following two injections of the loading dose. After a single injection of triamcinolone the beneficial initial effect on the macula edema faded within 3 months. Subretinal fluid and INL cystoid spaces diminished early in the course of treatment while fluid accumulation in the ONL seemed to be more persistent in both treatment arms. In FA, the area of leakage diminished significantly in both treatment arms. After repeated injections the morphologic OCT and FA characteristics of the treatment arms converged.Despite the higher dosage of triamcinolone, both therapies were safe and effective for treating diabetic macular edema. Fluid accumulation in the INL and subretinal space was more responsive to therapy than fluid accumulation in the ONL. Clinicaltrials.gov : NCT00682539.

Project description:ObjectiveTo provide data on the short-term effect of intravitreal bevacizumab for diabetic macular edema (DME).DesignRandomized phase II clinical trial.ParticipantsOne hundred twenty-one eyes of 121 subjects (109 eligible for analysis) with DME and Snellen acuity equivalent ranging from 20/32 to 20/320.InterventionsRandom assignment to 1 of 5 groups: (A) focal photocoagulation at baseline (n = 19), (B) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks (n = 22), (C) intravitreal injection of 2.5 mg of bevacizumab at baseline and 6 weeks (n = 24), (D) intravitreal injection of 1.25 mg of bevacizumab at baseline and sham injection at 6 weeks (n = 22), or (E) intravitreal injection of 1.25 mg of bevacizumab at baseline and 6 weeks with photocoagulation at 3 weeks (n = 22).Main outcome measuresCentral subfield thickness (CST) on optical coherence tomography and best-corrected visual acuity (VA) were measured at baseline and after 3, 6, 9, 12, 18, and 24 weeks.ResultsAt baseline, median CST was 411 mum and median Snellen VA equivalent was 20/50. Compared with group A, groups B and C had a greater reduction in CST at 3 weeks and about 1 line better median VA over 12 weeks. There were no meaningful differences between groups B and C in CST reduction or VA improvement. A CST reduction > 11% (reliability limit) was present at 3 weeks in 36 of 84 (43%) bevacizumab-treated eyes and 5 of 18 (28%) eyes treated with laser alone, and at 6 weeks in 31 of 84 (37%) and 9 of 18 (50%) eyes, respectively. Combining focal photocoagulation with bevacizumab resulted in no apparent short-term benefit or adverse outcomes. Endophthalmitis developed in 1 eye. The following events occurred during the first 24 weeks in subjects treated with bevacizumab without attributing cause to the drug: myocardial infarction (n = 2), congestive heart failure (n = 1), elevated blood pressure (n = 3), and worsened renal function (n = 3).ConclusionThese results demonstrate that intravitreal bevacizumab can reduce DME in some eyes, but the study was not designed to determine whether treatment is beneficial. A phase III trial would be needed for that purpose.

Project description:PurposeTo assess how patient choices (out-of-pocket costs, insurance plan, geographic region) impact initiation of therapy for diabetic macular edema (DME).DesignRetrospective cohort study using administrative medical claims data from a large, national insurer.ParticipantsAll patients newly diagnosed with DME from 2013 through 2016 were observed for 90 days after diagnosis or until first treatment was received.MethodsMultivariate logistic regression was used to create odds ratios comparing different baseline demographic and patient-related factors.Main outcome measuresThe primary outcome was the odds of receiving the different possible initial treatments for DME (anti-vascular endothelial growth factor [VEGF], focal laser treatment, steroids, or observation), no treatment, and not following up.ResultsOf the 6220 newly diagnosed DME patients, 3010 (48.4%) underwent a follow-up examination within 90 days of diagnosis, and of those, 1453 patients (48.3%) received treatment in the observation window, including 614 (20.4%) with bevacizumab, 191 (6.3%) with ranibizumab or aflibercept, 560 (18.6%) with focal laser, 38 (1.3%) with steroid injection, and 50 (1.7%) with an injection of an unspecified drug. Having a copay (vs. $0) lowered the odds of receiving any treatment (odds ratio [OR] = 0.60; 95% confidence interval [CI], 0.51-0.71; P < 0.001) and of receiving each treatment individually (anti-VEGF treatment: OR = 0.72; 95% CI, 0.59-0.88; bevacizumab: OR = 0.73; 95% CI, 0.59-0.91; ranibizumab or aflibercept: OR, 0.70; 95% CI, 0.49-0.99; focal laser: OR = 0.44; 95% CI, 0.35-0.55; P < 0.001). Contrary to having a copay, having a high deductible and type of insurance plan were not associated with initiating treatment (P > 0.41 for all comparisons). Patients in the Northeast showed lower odds of initiating anti-VEGF treatment (OR = 0.60; 95%CI, 0.44-0.82; P < 0.001) and specifically bevacizumab (OR = 0.47; 95% CI, 0.33-0.67; P < 0.001). Furthermore, Northeast patients who were treated with anti-VEGF showed a higher odds of receiving ranibizumab or aflibercept compared with bevacizumab (OR = 2.39; 95% CI, 1.31-4.37; P < 0.001). Southern Midwest patients showed a higher odds of treatment (anti-VEGF: OR = 1.35; 95%CI, 1.02-1.77; P < 0.001; bevacizumab: OR = 1.40; 95% CI, 1.04-1.87; focal laser: OR = 1.39; 95% CI, 1.01-1.89; P < 0.001).ConclusionsPatient choices such as copays and where they live are important factors in determining the initial choice of treatment for DME.

Project description:The prevalence of persistent diabetic macular edema (DME) after months of anti-vascular endothelial growth factor therapy and its effect on visual acuity are unknown.To assess subsequent outcomes of eyes with DME persisting for 24 weeks after initiating treatment with 0.5 mg of ranibizumab.We performed post hoc, exploratory analyses of a randomized clinical trial from March 20, 2007, through January 29, 2014, from 117 of 296 eyes (39.5%) randomly assigned to receive ranibizumab with persistent DME (central subfield thickness ?250 ?m on time domain optical coherence tomography) through the 24-week visit.Four monthly intravitreous injections of ranibizumab and then as needed per protocol.Cumulative 3-year probabilities of chronic persistent DME (failure to achieve a central subfield thickness <250 ?m and at least a 10% reduction from the 24-week visit on at least 2 consecutive study visits) determined by life-table analyses, and at least 10 letter (?2 line) gain or loss of visual acuity among those eyes.The probability of chronic persistent DME among eyes with persistent DME at the 24-week visit decreased from 100% at the 32-week visit to 81.1% (99% CI, 69.6%-88.6%), 55.8% (99% CI, 42.9%-66.9%), and 40.1% (99% CI, 27.4%-52.4%) at the 1-, 2-, and 3-year visits, respectively. At 3 years, visual acuity improved in eyes with and without chronic persistent DME through the follow-up period, respectively, by a mean of 7 letters and 13 letters from baseline. Among 40 eyes with chronic persistent edema through 3 years, 17 (42.5%) (99% CI, 23.1%-63.7%) gained 10 letters or more from baseline, whereas 5 (12.5%) (99% CI, 2.8%-31.5%) lost 10 letters or more from baseline.These data suggest less than half of eyes treated for DME with intravitreous ranibizumab have persistent central-involved DME through 24 weeks after initiating treatment. Among the 40% that then have chronic persistent central-involved DME through 3 years, longer-term visual acuity outcomes appear to be slightly worse than in the 60% in which DME does not persist. Nevertheless, when following the treatment protocol used in this trial among eyes with vision impairment from DME, long-term improvement in visual acuity from baseline is typical and substantial (?2-line) loss of visual acuity is likely uncommon through 3 years, even when central-involved DME chronically persists.

Dataset Information

Oral minocycline for the treatment of diabetic macular edema (DME): results of a phase I/II clinical study.

Publications

Oral minocycline for the treatment of diabetic macular edema (DME): results of a phase I/II clinical study.

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