All Posts tagged Trial

Retinal Physician Clinical Trial Update

Dry AMD

Study: A Phase 2/3 Trial to Assess the Safety and Efficacy of Intravitreous Administration of Zimura (Anti-C5 Aptamer) in Subjects With Geographic Atrophy Secondary to Dry Age-Related Macular Degeneration

Sponsor: Ophthotech

Purpose: To evaluate the safety and efficacy of intravitreous administration of Zimura when administered in subjects with geographic atrophy (GA) secondary to dry age-related macular degeneration

Design: Randomized, Safety/Efficacy, Parallel Assignment, Double Blind

Number of Patients: 300

Inclusion Criteria: Diagnosis of non-foveal GA secondary to dry AMD

Exclusion Criteria: Retinal atrophy involving the fovea; evidence of CNV; any prior treatment for AMD or any prior intravitreal treatment for any indication in either eye, except oral supplements of vitamins and minerals; any intraocular surgery or thermal laser within 3 months of trial entry; any prior thermal laser in the macular region, regardless of indication; any ocular or periocular infection in the 12 weeks prior to entry; previous therapeutic radiation in the region of the study eye; any sign of diabetic retinopathy in either eye

Full Paper: Retinal Physician Clinical Trial Update
(206K PDF)

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Trends of Anti-Vascular Endothelial Growth Factor Use in Ophthalmology Among Privately Insured and Medicare Advantage Patients

Purpose: To characterize the first 10 years of intravitreal anti-vascular endothelial growth factor (VEGF) medication use for ophthalmic disease, including bevacizumab, ranibizumab, and aflibercept.

Design: A retrospective cohort study using administrative claims data from January 1, 2006 to December 31, 2015.

Subjects: Total of 124 835 patients 18 years of age or over in the United States.

Methods: OptumLabs Data Warehouse, which includes administrative claims data for over 100 million commercially insured and Medicare Advantage individuals, was used to identify patients receiving intravitreal anti-VEGF injections based on Current Procedural Terminology codes.

Main Outcome Measures: Total and annual numbers of intravitreal anti-VEGF injections, as well as injections per 1000 enrolled patients per general category of ophthalmic disease, overall and for each available medication.

Results: There were 959 945 anti-VEGF injections among 124 835 patients from 2006 to 2015. Among all injections, 64.6% were of bevacizumab, 22.0% ranibizumab, and 13.4% aflibercept; 62.7% were performed to treat age-related macular degeneration (AMD), 16.1% to treat diabetic retinal diseases (including 0.9% of all injections that were for proliferative diabetic retinopathy), 8.3% to treat retinal vein occlusions, and 12.9% for all other uses. Use of bevacizumab and ranibizumab for AMD plateaued as of 2011/2012 and decreased thereafter (in 2006, 58.8 and 35.3 injections/1000 AMD patients, respectively; in 2015, 294.4 and 100.7 injections/1000), whereas use of aflibercept increased (1.1 injections/1000 AMD patients in 2011 to 183.0 injections/1000 in 2015). Bevacizumab use increased each year for diabetic retinal disease (2.4 injections/1000 patients with diabetic retinal disease in 2009 to 13.6 per 1000 in 2015) while that of ranibizumab initially increased significantly and then declined after 2014 (0.1 in 2009 to 4.0 in 2015). Aflibercept use increased each year in patients with diabetic etinal diseases and retinal vein occlusions (both >0.1 per 1000 retinal vein occlusion patients in 2011, 5.6 and 140.2 in 2015).

Conclusions: Intravitreal injections of anti-VEGF medications increased annually from 2006 to 2015. Bevacizumab was the most common medication used, despite its lacking U.S. Food and Drug Administration approval to treat ophthalmic disease, and AMD was the most common condition treated. Ranibizumab use declined after 2014 while both the absolute and relative use of bevacizumab and aflibercept increased. Ophthalmology 2017;124:352-358 ª 2016 by the American Academy of Ophthalmology

Full Paper: Trends of Anti-Vascular Endothelial Growth Factor Use in Ophthalmology Among Privately Insured and Medicare Advantage Patients
(599K PDF)

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Extent of Internal Limiting Membrane Peeling and its Impact on Macular Hole Surgery Outcomes: A Randomized Trial

Since Kelly and Wendel introduced the victrectomy technique to reattach the macular hole (MH),1 considerable advances in surgical treatment have been achieved. As a consequence, MH has now become a surgically treatable disease with standardized techniques incorporating vitrectomy, induction of posterior vitreous detachment, internal limiting membrane (ILM) peeling, and gas tamponade.2 Although there was a debate on ILM peeling in the past, ILM peeling has been established to improve surgical success rates.3–6 In addition, retinal ILM peeling has been facilitated by staining dye such as indocyanine green.7,8

The rationale for ILM peeling is that MH can occur and enlarge owing to contraction of perifoveal vitreous and cellular constituents with myofibroblastic differentiation on the surface of the ILM.2,9 Although ILM has no inherent contractile properties, it does act as a scaffold for contractile tissue to exert tangential traction on fovea. Several studies using optical coherence tomography (OCT) have reported the dynamic sealing process after MH surgery.10–13 Foveal tissue elongation and macular migration have been noted following ILM peeling after surgery for MH and diabetic macular edema.14–17 In addition, there is a significant correlation between these morphologic changes and visual function such as metamorphopsia.14

Although ILM peeling has become a widely accepted surgical technique since the introduction of MH surgery, the optimal extent of ILM peeling is not known and the anatomic and functional outcomes according to peeling extent have not been investigated. The purpose of this study was to investigate the influence of the extent of ILM peeling on anatomic and functional outcomes of MH surgery.

Full Paper: Extent of Internal Limiting Membrane Peeling and its Impact on Macular Hole Surgery Outcomes: A Randomized Trial
(1.3M PDF)

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Cost-effectiveness of Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema Treatment

Arecent Diabetic Retinopathy Clinical Research Network (DRCR.net) comparative effectiveness trial found that for patients with diabetic macular edema (DME) and approximate Snellen equivalent baseline visual acuity (VA) of 20/50 or worse aflibercept produced greater mean VA gains at 1 year than bevacizumab or ranibizumab. In contrast, no difference in mean VA improvement was identified for patients with baseline VAs of 20/32 to 20/40.1

These agents also vary substantially in cost. O nthe basis of 2015 wholesale acquisition costs, aflibercept (2.0 mg) costs $1850,2 ranibizumab (0.3mg) costs $1170,2 and bevacizumab repackaged at compounding pharmacies into syringes for ophthalmologic use containing 1.25mg of bevacizumab costs approximately $6 0per dose.3 Considering that these medicines may be given 9 to 11 times in the first year of treatment1 and, on average, 17 times during 5 years,4 total costs can be substantial. In 2010, when these intravitreous agents were being used predominantly for age-related macular degeneration, ophthalmologic use of anti–vascular endothelial growth factor (VEGF)therapy cost approximately $2 billion or one-sixth of the entire Medicare Part B drug budget.3 In 2013, Medicare Part B expenditures for aflibercept and ranibizumab alone totaled $2.5 billion.5 Given these costs, the DRCR.net investigators believed it was important to analyze the relative cost-effectiveness of treating DME using each agent.

Full Paper: Cost-effectiveness of Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema Treatment
(385K PDF)

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Conversion to Aflibercept After Prior Anti-VEGF Therapy for Persistent Diabetic Macular Edema

Diabetic Macular Edema (DME) is the leading cause of visual impairment in patients with diabetic retinopathy.1 In 2010, approximately 20.6 million out of a projected 92.6 million adults with diabetic retinopathy worldwide were estimated to have concurrent DME.2 This global healthcare burden will likely continue to increase at alarming rates, as some models estimate the number of diabetics will double by the year 2030.3

With the Early Treatment Diabetic Retinopathy Study (ETDRS) in the 1980s,4 macular laser photocoagulation became the mainstay of DME management, and it remained the standard of care in the decades that followed. The advent of intravitreal pharmacotherapy agents, primarily driven by the class of vascular endothelial growth factor (VEGF) inhibitors, has since revolutionized how this condition is treated. Validated through the RISE and RIDE phase 3 clinical trials,5 ranibizumab (Lucentis; Genentech, South San Francisco, California, USA) became the first VEGF inhibitor approved by the Food & Drug Administration (FDA) for this indication in 2012.

While off-label, bevacizumab (Avastin; Genentech) has been evaluated through smaller trials, such as the BOLT study.6 Most recently, aflibercept (Eylea; Regeneron, Tarrytown, New York) gained FDA approval to treat DME in July 2014 with the VIVID and VISTA phase 3 clinical trials.7,8

While there is ample evidence supporting the safety and efficacy of the 3 anti-VEGF agents in the management of DME, a head-to-head comparison only recently became available when the Diabetic Retinopathy Clinical Research Network (DRCR) published the 1-year outcomes of its Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab, and Ranibizumab for DME (Protocol T).9 The results demonstrated that when baseline visual acuity (VA) loss was mild (›20/ 40), there was no clinical difference between the 3 medications. However, when the initial acuity loss was more severe (‹20/50), a greater visual benefit was derived from aflibercept.9

Since the FDA approval of aflibercept for DME, and in light of Protocol T’s findings, many retinal specialists are converting eyes from ranibizumab or bevacizumab to aflibercept with the goal of optimizing treatment outcomes, particularly in cases of refractory DME. In the current study, we evaluated the short-term functional and anatomic responses of patients with persistent DME after multiple previous anti-VEGF injections that were converted to aflibercept therapy.

Full Paper: Conversion to Aflibercept After Prior Anti-VEGF Therapy for Persistent Diabetic Macular Edema
(1.78M PDF)

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Influence of the Vitreomacular Interface on Treatment Outcomes in the Comparison of Age-Related Macular Degeneration Treatments Trials

The role of the vitreomacular interface (VMI) in the pathophysiologic features and treatment of neovascular age-related macular degeneration (AMD) has generated much recent interest. In retrospective and prospective observational case series, a higher prevalence of vitreomacular adhesion (VMA) has been reported in eyes with neovascular AMD compared with eyes with nonneovascular AMD.1-3 In a paired eye study, VMA was observed more frequently in eyes with neovascular AMD compared with the fellow nonneovascular AMD eye that served as a control.4 Some investigators also have observed that VMA occurs at the vitreoretinal interface overlying the choroidal neovascularization (CNV).1,2,4 Vitreomacular adhesion also influences treatment and outcomes in neovascular AMD; the absence of VMA has been associated with slightly better visual acuity (VA),5,6 and eyes with VMA may require more frequent dosing compared with neovascular AMD eyes without VMA.5,6 This combined body of evidence suggests thatVMA may have a role in the pathogenesis and management of CNV.

The purpose of our study was to assess the relationship of the VMI to treatment frequency in neovascular AMD, as well as to VA and anatomic outcomes in the Comparison of AMD Treatments Trials (CATT),7 one of the largest prospective treatment trials for neovascular AMD conducted to date.

Full Paper: Influence of the Vitreomacular Interface on Treatment Outcomes in the Comparison of Age-Related Macular Degeneration Treatments Trials
(319K PDF)

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Ocriplasmin Injection

Two recent articles published in the Archives of Ophthalmology expose the risks of Ocriplasmin injection into the vitreous:

1. Acute Panretinal Structural and Functional Abnormalities After Intravitreous Ocriplasmin Injection — JAMA Ophthalmol. 2014;132(4):484-486.

Conclusion: Retinal dysfunction associated with intravitreous ocriplasmin injection is not limited to the macular region and seems to involve the entire retina. Enzymatic cleavage of intraretinal laminin is a biologically plausible mechanism for acute ocriplasmin retinal toxic effects.

2. Vision Loss After Intravitreal Ocriplasmin: Correlation of Spectral-Domain Optical Coherence Tomography and Electroretinography — JAMA Ophthalmol. 2014;132(4):487-490.

Conclusion: On the basis of these findings, it is possible that ocriplasmin may have a diffuse enzymatic effect on photoreceptors or the retinal pigment epithelium that is not limited to areas of vitreomacular adhesion. The rod photoreceptors may be more susceptible than cone photoreceptors to the effects of ocriplasmin. Further work is needed to understand mechanisms of visual impairment after ocriplasmin.

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JETREA® (ocriplasmin) by ThromboGenics

JETREA® (ocriplasmin) by ThromboGenics

Development of OCT (optic coherence tomography) has help clinicians gain a better understanding of the critical role played by the vitreous in macular and retinal vascular diseases.

With early-stage PVD (posterior vitreous detachment), fibrocellular organization of vitreous remnants left on the retinal surface during vitreoretinal separation is the most likely cause of idiopathic epiretinal membrane.

There has been a longstanding interest in developing pharmacologic methods for nonsurgical induction of PVD, a technique known as pharmacologic vitreolysis. Pharmacologic agents are candidates for vitreolysis if they have the ability to induce vitreous liquefaction, weakening the vitreoretinal adhesion or both. A variety of agents have been studies to date, including:

  • Collagenase
  • Chondroitinase
  • Dispase
  • Hyaluronidase
  • Nattohinase
  • Plasmin
  • Tissue plasminogen activator
  • Vitreosolve (Vitreoretinal Technologies, Inc., Irvin, CA)
  • Arginine-glycerine-aspartate peptide.
  • Ocriplasmin (formally microcplasmin)

Recently, two, Phase-3 clinical trials of ocriplasmin in patients with symptomatic vitreomacular adhesions were completed.

Vitreomacular adhesion (VMA) at the macula causes metamorphopsia or visual distortion. Ocriplasmin by ThromboGenics is the only agent that induces both liquefaction and separation of the vitreous from the retinal interface.

Ocriplasmin Efficacy

VMA = VMT

  • Pharmacologic resolution of VMA at 28 days was 26.5%.
  • Placebo group (p‹0.001) was 10.1%.
  • If patients with epiretinal membranes were excluded, 34.5% versus 14.3%.

Side Effects

There were 7.7% who had unexplained visual loss, which resolved within six months. Other side effects included:

  • Floaters – 13%
  • Eye pain – 10.5%
  • Photopsia – 10%
  • Blurred vision – 6.5%

Less than robust results of the ocriplasmin trials point to the complexity of pharmacologic vitreolysis and suggest that the ideal vitreolytic agent, or combination of agents, has yet to be identified. Other options would include:

  • Intravitreal gas injection (pneumatic vitreolysis)
  • Vitreous surgery

Vitreous surgery currently remains the gold standard for treating significant vitreomacular disorders and likely will continue to be the preferred treatment for some time.

The perfect vitreolytic drug capable of inducing PVDs consistently with a clear retinal surface and no toxicity concerns would be the preferred treatment.

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