OR2806 Levosulpiride-Induced Hyperprolactinemia For The Treatment Of Diabetic Macular Edema: A Phase 2 Pilot Clinical Trial
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PROVIDER: S-EPMC10553706 | biostudies-literature | 2023 Oct
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Project description:Background/objectiveThe prokinetic levosulpiride elevates vasoinhibin levels in the vitreous of patients with proliferative diabetic retinopathy (PDR) suggesting clinical benefits due to the anti-vasopermeability and anti-angiogenic properties of vasoinhibin. We investigated the biological activity of levosulpiride in centre-involving diabetic macular oedema (DME).Patients/methodsProspective, randomized, double-blinded, dual-centre, phase 2 trial in patients with centre-involving DME orally treated with placebo (n = 17) or levosulpiride (n = 17) for 8 weeks or in patients with PDR undergoing elective pars plana vitrectomy and receiving placebo (n = 18) or levosulpiride (n = 18) orally for the 1 week before vitrectomy.ResultsLevosulpiride improved changes from baseline in best-corrected visual acuity (p ≤ 0.037), central foveal thickness (CFT, p ≤ 0.013), and mean macular volume (MMV, p ≤ 0.002) at weeks 4, 6, and 8 compared to placebo. At 8 weeks, the proportion of eyes gaining ≥5 ETDRS letters at 4 m (41% vs. 28%), losing ≥21 μm in CFT (55% vs. 28%), and dropping ≥0.06 mm3 in MMV (65% vs. 29%) was higher after levosulpiride than placebo. The overall grading of visual and structural parameters improved with levosulpiride (p = 0.029). Levosulpiride reduced VEGF (p = 0.025) and PlGF (p = 0.008) levels in the vitreous of PDR patients. No significant adverse side-effects were detected.ConclusionsOral levosulpiride for 8 weeks improved visual and structural outcomes in patients with centre-involving DME by mechanisms that may include intraocular upregulation of vasoinhibin and downregulation of VEGF and PlGF. Larger clinical trials evaluating long-term efficacy and safety are warranted.
| S-EPMC10858020 | biostudies-literature
Project description:PurposeThe Diabetic Macular Edema Treated with Ozurdex (DMEO) Trial measured aqueous pro-permeability factors (PPFs) in diabetic macular edema (DME) patients before and after injection of dexamethasone implant or vascular endothelial growth factor (VEGF)-neutralizing protein and correlated changes in levels with changes in excess foveal thickness (EFT) to identify potential PPFs contributing to DME.DesignProspective, randomized crossover clinical trial.MethodsTwenty DME patients randomized to dexamethasone implant or VEGF-neutralizing protein had aqueous taps and spectral-domain optical coherence tomography (SDOCT) at baseline and every 4 weeks for 28 weeks. Aqueous levels of 55 vasoactive proteins were measured with protein array. Crossover at week 16 provided changes in protein levels after each intervention in all 20 patients.ResultsAfter dexamethasone implant there was significant correlation between changes in levels of 13 vasoactive proteins with changes in EFT, including 3 known PPFs: angiopoietin-2 (r = 0.40, P = .001), hepatocyte growth factor (HGF; r = 0.31, P = .02), and endocrine gland-VEGF (EG-VEGF, r = 0.43, P < .001). Reduction of prolactin, insulin-like growth factor binding protein-3, and matrix metalloproteinase-9 correlated with edema reduction after injection of a VEGF-neutralizing protein as well as dexamethasone implant, suggesting their modulation is likely secondary to changes in edema rather than causative.ConclusionsCorrelation of edema reduction with reduction in the PPFs angiopoietin-2, HGF, and EG-VEGF provides potential insight into the multifactorial molecular mechanism by which dexamethasone implants reduce edema and suggest that additional study is needed to investigate the contributions of these 3 factors to chronic DME.
| S-EPMC5482180 | biostudies-literature
Project description:Diabetic macular edema is the most common cause of visual impairment in patients with diabetes mellitus. The pathogenesis of macular edema is complex and multifactorial. For many years, laser photocoagulation has been considered the standard therapy for the treatment of diabetic macular edema; however, few patients achieve significant improvements in visual acuity. Today the intravitreal administration of anti-inflammatory or anti-angiogenic agents together with the use of laser photocoagulation represents the standard of care for the treatment of this complication. The intravitreal route of administration minimizes the systemic side effects of corticosteroids. Steroid-related ocular side effects are elevated intraocular pressure and cataract, while injection-related complications include endophthalmitis, vitreous hemorrhage, and retinal detachment. In order to reduce the risks and complications, intravitreal implants have been developed recently to provide sustained release of corticosteroids and reduce repeated injections for the management of diabetic macular edema. In this review, the efficacy, safety, and therapeutic potential of intravitreal corticosteroids in diabetic macular edema are discussed with a review of recent literature.
| S-EPMC5468529 | biostudies-other
Project description:Evaluating the effects of cibinetide in diabetic macular edema (DME). Phase 2 trial. Naïve patients with >400 µm central retinal thickness (CRT) DME in one/both eyes were recruited (May 2016-April 2017) at the Belfast Health and Social Care Trust. The study eye was that with best vision and lowest CRT. Patients self-administered cibinetide 4 mg/day subcutaneously for 12 weeks. Primary and secondary outcomes: mean change from baseline to week 12 in best corrected visual acuity (BCVA), CRT, central retinal sensitivity, tear production, patient-reported outcomes, adverse events and antibodies to cibinetide. Descriptive statistics were used; exploratory analyses focused on non-study eyes, diabetic control, serum cytokines and albuminuria. Nine patients were recruited; eight completed the study. There was no improvement in mean change baseline-week 12 in BCVA (-2.9 + 5.0), CRT (10 + 94.6 microns), central retinal sensitivity (-0.53 + 1.9 dB) or tear production (-0.13 + 7.7 mm), but there was an improvement in National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite scores (2.7 + 3.1). Some participants experienced improvements in CRT, tear production, diabetic control and albuminuria. No serious adverse events/reactions or anti-cibinetide antibodies were seen. The cibinetide 12-week course was safe. Improvements in NEI VFQ-25 scores, CRT, tear production, diabetic control and albuminuria, observed in some participants, warrant further investigation. EudraCT number: 2015-001940-12. ISRCTN16962255-registration date 25.06.15.
| S-EPMC7408632 | biostudies-literature
Project description:BackgroundDiabetic retinopathy (DR) and diabetic macular edema (DME) are potentially blinding, microvascular retinal diseases in people with diabetes mellitus. Preclinical studies support a protective role of the hormone prolactin (PRL) due to its ocular incorporation and conversion to vasoinhibins, a family of PRL fragments that inhibit ischemia-induced retinal angiogenesis and diabetes-derived retinal vasopermeability. Here, we describe the protocol of an ongoing clinical trial investigating a new therapy for DR and DME based on elevating the circulating levels of PRL with the prokinetic, dopamine D2 receptor blocker, levosulpiride.MethodsIt is a prospective, randomized, double-blind, placebo-controlled trial enrolling male and female patients with type 2 diabetes having DME, non-proliferative DR (NPDR), proliferative DR (PDR) requiring vitrectomy, and DME plus standard intravitreal therapy with the antiangiogenic agent, ranibizumab. Patients are randomized to receive placebo (lactose pill, orally TID) or levosulpiride (75 mg/day orally TID) for 8 weeks (DME and NPDR), 1 week (the period before vitrectomy in PDR), or 12 weeks (DME plus ranibizumab). In all cases the study medication is taken on top of standard therapy for diabetes, blood pressure control, or other medical conditions. Primary endpoints in groups 1 and 2 (DME: placebo and levosulpiride), groups 3 and 4 (NPDR: placebo and levosulpiride), and groups 7 and 8 (DME plus ranibizumab: placebo and levosulpiride) are changes from baseline in visual acuity, retinal thickness assessed by optical coherence tomography, and retinal microvascular abnormalities evaluated by fundus biomicroscopy and fluorescein angiography. Changes in serum PRL levels and of PRL and vasoinhibins levels in the vitreous between groups 5 and 6 (PDR undergoing vitrectomy: placebo and levosulpiride) serve as proof of principle that PRL enters the eye to counteract disease progression. Secondary endpoints are changes during the follow-up of health and metabolic parameters (blood pressure, glycated hemoglobin, and serum levels of glucose and creatinine). A total of 120 patients are being recruited.DiscussionThis trial will provide important knowledge on the potential benefits and safety of elevating circulating and intraocular PRL levels with levosulpiride in patients with DR and DME.Ethics and disseminationEthics approval has been obtained from the Ethics Committees of the National University of Mexico (UNAM) and the Instituto Mexicano de Oftalmología, I.A.P. Dissemination will include submission to peer-reviewed scientific journals and presentation at congresses.Clinical trial registrationRegistered at www.ClinicalTrials.gov, ID: NCT03161652 on May 18, 2017.
| S-EPMC5986911 | biostudies-literature
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.
| S-EPMC2245885 | biostudies-literature
Project description:BackgroundMacular edema is the most common cause of vision loss among patients with diabetes.ObjectiveTo determine the cost-effectiveness of different treatments of diabetic macular edema (DME).DesignMarkov model.Data sourcesPublished literature and expert opinion.Target populationPatients with clinically significant DME.Time horizonLifetime.PerspectiveSocietal.InterventionLaser treatment, intraocular injections of triamcinolone or a vascular endothelial growth factor (VEGF) inhibitor, or a combination of both.Outcome measuresDiscounted costs, gains in quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs).Results of base-case analysisAll treatments except laser monotherapy substantially reduced costs, and all treatments except triamcinolone monotherapy increased QALYs. Laser treatment plus a VEGF inhibitor achieved the greatest benefit, gaining 0.56 QALYs at a cost of $6975 for an ICER of $12 410 per QALY compared with laser treatment plus triamcinolone. Monotherapy with a VEGF inhibitor achieved similar outcomes to combination therapy with laser treatment plus a VEGF inhibitor. Laser monotherapy and triamcinolone monotherapy were less effective and more costly than combination therapy.Results of sensitivity analysisVEGF inhibitor monotherapy was sometimes preferred over laser treatment plus a VEGF inhibitor, depending on the reduction in quality of life with loss of visual acuity. When the VEGF inhibitor bevacizumab was as effective as ranibizumab, it was preferable because of its lower cost.LimitationLong-term outcome data for treated and untreated diseases are limited.ConclusionThe most effective treatment of DME is VEGF inhibitor injections with or without laser treatment. This therapy compares favorably with cost-effective interventions for other conditions.Primary funding sourceAgency for Healthcare Research and Quality.
| S-EPMC4020006 | biostudies-literature
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.
| S-EPMC6875609 | biostudies-literature
Project description:Purpose of reviewThis review highlights indications and evidence on laser therapy in the management of diabetic retinopathy and diabetic macular edema. Particular focus is placed upon the benefits and limitations of conventional laser photocoagulation versus more modern laser photocoagulation techniques, as well as the role of laser photocoagulation in treatment of diabetic retinopathy and diabetic macular edema with the frequent utilization of pharmacologic, including anti-vascular endothelial growth factor (VEGF), therapy.Recent findingsLaser photocoagulation remains the gold-standard therapy for the effective, definitive treatment of PDR, and also is highly effective in the management of DME. However, numerous recent studies have demonstrated the clinical efficacy and improved functional and anatomic outcomes of combination therapy with pharmacologic treatment. Continuing innovations in laser technology and improved understanding of laser-retinal interactions and pathophysiology demonstrate that laser therapy will continue to play a critical role in the treatment of diabetic retinopathy and diabetic macular edema for many years to come.
| S-EPMC8420141 | biostudies-literature
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.
| S-EPMC4786449 | biostudies-literature