Marla B. Sultan

A Phase 2/3, Multicenter, Randomized, Double-Masked, 2-Year Trial of Pegaptanib Sodium for the Treatment of Diabetic Macular Edema

PURPOSE To confirm the safety and compare the efficacy of intravitreal pegaptanib sodium 0.3 mg versus sham injections in subjects with diabetic macular edema (DME) involving the center of the macula associated with vision loss not due to ischemia. DESIGN Randomized (1:1), sham-controlled, multicenter, parallel-group trial. PARTICIPANTS Subjects with DME. INTERVENTION Subjects received pegaptanib 0.3 mg or sham injections every 6 weeks in year 1 (total = 9 injections) and could receive focal/grid photocoagulation beginning at week 18. During year 2, subjects received injections as often as every 6 weeks per prespecified criteria. MAIN OUTCOME MEASURES The primary efficacy endpoint was the proportion gaining ≥ 10 letters of visual acuity (VA) from baseline to year 1. Safety was monitored throughout. RESULTS In all, 260 (pegaptanib, n = 133; sham, n = 127) and 207 (pegaptanib, n = 107; sham, n = 100) subjects were included in years 1 and 2 intent-to-treat analyses, respectively. A total of 49 of the 133 (36.8%) subjects from the pegaptanib group and 25 of the 127 (19.7%) from the sham group experienced a VA improvement of ≥ 10 letters at week 54 compared with baseline (odds ratio [OR], 2.38; 95% confidence interval, 1.32-4.30; P = 0.0047). For pegaptanib-treated subjects, change in mean VA from baseline by visit was superior (P<0.05) to sham at weeks 6, 24, 30, 36, 42, 54, 78, 84, 90, 96, and 102. At week 102, pegaptanib-treated subjects gained, on average, 6.1 letters versus 1.3 letters for sham (P<0.01). Fewer pegaptanib- than sham-treated subjects received focal/grid laser treatment (week 54, 31/133 [23.3%] vs 53/127 [41.7%], respectively, P = 0.002; week 102, 27/107 [25.2%] vs 45/100 [45.0%], respectively, P = 0.003). The pegaptanib treatment group showed significantly better results on the National Eye Institute-Visual Functioning Questionnaire than sham for subscales important in this population. Pegaptanib was well tolerated; the frequencies of discontinuations, adverse events, treatment-related adverse events, and serious adverse events were comparable in the pegaptanib and sham groups. CONCLUSIONS Patients with DME derive clinical benefit from treatment with the selective vascular endothelial growth factor antagonist pegaptanib 0.3 mg. These findings indicate that intravitreal pegaptanib is effective in the treatment of DME and, taken together with prior study data, support a positive safety profile in this population. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Understanding the importance of IOP variables in glaucoma: a systematic review.

Glaucoma is one of the leading causes of visual impairment and blindness. Lowering intraocular pressure (IOP) is the only proven means to slow or halt disease progression among those at higher risk of developing glaucoma and those with early to moderate or more advanced glaucoma. Recent publications have highlighted the potential for increased rates or likelihood of worsening glaucoma among those with larger IOP swings within defined time periods. The purpose of this systematic, comprehensive review and analysis of the literature was to assess the state of knowledge in the area of IOP changes over time and the potential impact of such changes on treatment. Current literature indicates that a random IOP measurement is a poor surrogate for IOP levels throughout the day and across visits. We address several key questions: 1) What is the best way to measure IOP? 2) Should multiple IOP measurements be performed in a day in the office (short-term IOP fluctuation)? 3) Is measurement at night required? 4) Should clinicians begin to assess long-term IOP fluctuation in patients under stable treatment (across days or visits)? and 5) Should therapy choices be influenced by properties of different treatment options relative to short- or long-term IOP fluctuation?

Changes in vision- and health-related quality of life in patients with diabetic macular edema treated with pegaptanib sodium or sham.

PURPOSE To compare vision function and self-reported quality of life (QoL) in patients with diabetic macular edema (DME) treated with intravitreous pegaptanib 0.3 mg or sham injection. METHODS This randomized (1:1), controlled, multicenter trial included subjects with DME (center point thickness on OCT, ≥ 250 μm) and visual acuity (VA) ≤ 65 letters and ≥ 35 letters. In year 1, pegaptanib or sham was administered every 6 weeks with focal/grid photocoagulation at investigator discretion after week 18. Subjects received injections as often as every 6 weeks per pre-specified criteria in year 2. Primary efficacy endpoint: proportion gaining ≥10 letters of VA from baseline to week 54. Change in QoL from baseline to weeks 54 and 102 was assessed with the 25-item National Eye Institute-Visual Function Questionnaire (NEI-VFQ 25) and the EQ-5D. RESULTS One hundred thirty-three pegaptanib- and 127 sham-treated subjects were in the year 1 intent-to-treat population. From baseline to week 54, ≥ 10 letter gains seen in 49 (36.8%) pegaptanib- and 25 (19.7%) sham-treated subjects (odds ratio [95% CI]: 2.38 [1.32-4.30]; P = 0.0047). At 2 years, the VA trend favored pegaptanib. The NEI-VFQ 25 domains of Near Vision, Distance Vision, and Social Functioning (week 54) and Distance Vision, Social Functioning, Mental Health, and Composite Score (week 102) demonstrated clinically meaningful (>5-point between-group difference) and statistically significant (P < 0.05) benefits favoring pegaptanib. No significant difference in the mean change in generic EQ-5D-weighted utility scores was seen. CONCLUSIONS The VA improvement from pegaptanib treatment versus sham is reflected by improved vision-related QoL as reported by the DME patient (ClinicalTrials.gov number, NCT00605280).

Assessing the Importance of IOP Variables in Glaucoma Using a Modified Delphi Process.

PurposeTo assess the degree of consensus among glaucoma experts on the measurement, characterization, and potential implications of intraocular pressure (IOP) and its fluctuation for glaucoma treatment. MethodsA multinational panel of 9 glaucoma experts used a modified Delphi process to rate the level of agreement with 72 statements characterizing methods of measuring IOP, the importance of IOP reduction, and clinical implications of changes in IOP over time. After receiving a literature review, panelists rated each statement on a 9-point Likert scale. A panel meeting was held to discuss the ratings followed by a second round of independent ratings. Consensus and nonconsensus regarding the panels agreement with each statement were determined using a binomially distributed statistical definition. ResultsThe panel found consensus in 46% of 81 statements, nonconsensus in 6%, and indeterminate status in 48%. Categories having the highest proportion of statements with consensus were importance of IOP reduction (4/4 statements), importance of long-term IOP fluctuation and reduction (6/9), and impact of medication on short-term and long-term IOP fluctuation (6/10 for each). Indeterminate statements were distributed unevenly with 74% of statements related to IOP measurement rated indeterminate compared with 38% related to the clinical implications of short-term and long-term IOP fluctuation. ConclusionsA modified Delphi process was useful in identifying areas of consensus regarding IOP measurement and importance of IOP fluctuation among glaucoma experts. Concurrently, the need for additional investigations assessing the role of IOP changes in glaucoma management is highlighted by the indeterminate and nonconsensus ratings.

Long-term safety and efficacy of tafamidis for the treatment of hereditary transthyretin amyloid polyneuropathy: results up to 6 years

Abstract Background: The objective of the present study was to evaluate the long-term safety and efficacy of tafamidis in treating hereditary transthyretin amyloid polyneuropathy. Methods: A prospectively planned interim analysis was conducted on an on-going, phase III, open-label extension study following an 18-month, randomized, controlled study and 12-month, open-label extension study in ATTRV30M patients and a single-arm, open-label study in non-ATTRV30M patients. Thirty-seven ATTRV30M patients received placebo for 18 months, then switched to tafamidis and 38 ATTRV30M patients and 18 non-ATTRV30M patients continuously received tafamidis from day 1, up to 6 years. Results: Long-term tafamidis was associated with a favourable safety/tolerability profile, without any unexpected adverse events. Patients initiating tafamidis at the start of the randomized study had less polyneuropathy progression versus those switching to tafamidis following 18 months of placebo and were less likely to progress to the next ambulatory stage after up to 6 years follow-up. In the patients who switched from placebo to tafamidis, polyneuropathy progression and deterioration in quality of life slowed significantly during long-term tafamidis treatment as compared with the previous placebo treatment. In non-ATTRV30M patients, some polyneuropathy progression was observed across all efficacy measures. Conclusions: These data provide evidence for the long-term (up to 6 years) safety and efficacy of tafamidis.ClinicalTrials.gov: NCT00925002

Assessing the Efficacy of Latanoprost vs Timolol Using an Alternate Efficacy Parameter: The Intervisit Intraocular Pressure Range

PURPOSE To compare latanoprost and timolol with regard to changes in the intervisit intraocular pressure (IOP) range, a measure of long-term IOP fluctuation. DESIGN Post hoc analysis of three 6-month, multicenter, randomized (1:1), double-masked registration trials of latanoprost (n = 313) vs timolol (n = 318). METHODS Analyses included patients with glaucoma or ocular hypertension who instilled latanoprost once daily in the evening and vehicle in the morning and those instilling timolol twice daily. Pretreatment intervisit IOP range: highest IOP minus lowest IOP of 4 measurements obtained at screening and baseline. Posttreatment intervisit IOP range: highest IOP minus lowest IOP of 4 measurements obtained at weeks 18 and 26. Ranges were dichotomized to high (> 6 mm Hg) and low (< or = 6 mm Hg). RESULTS Both treatments resulted in significant reductions in mean intervisit IOP range during 26 weeks. Pretreatment, comparable proportions of patients treated with latanoprost and timolol had high intervisit IOP ranges (22% [70/313] and 23% [72/318], respectively; P = .934). After treatment, 6% (19/313) and 11% (35/318) of patients in the latanoprost and timolol groups, respectively, had high intervisit IOP ranges (P = .026). Significant risk factors for high posttreatment intervisit range (multivariate logistic regression) were high pretreatment intervisit IOP range, treatment with timolol, Black race, longer time since diagnosis, and higher mean pretreatment IOP. CONCLUSIONS Compared with timolol, treatment with latanoprost results in significantly fewer patients with a high IOP fluctuation. The impact of reducing high IOP fluctuation on progressive glaucomatous damage deserves further investigation in prospective studies.

Design and Rationale of the Phase 3 ATTR-ACT Clinical Trial (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial)

Transthyretin amyloidosis is a rare, life-threatening disease resulting from aggregation and deposition of transthyretin amyloid fibrils in various tissues. There are 2 predominate phenotypic presentations of the disease: transthyretin familial amyloid polyneuropathy, which primarily affects the peripheral nerves, and transthyretin cardiomyopathy (TTR-CM), which primarily affects the heart. However, there is a wide overlap with symptoms at presentation and disease course being highly variable and influenced by the underlying transthyretin mutation, age of the affected individual, sex, and geographic location. Treatment of transthyretin amyloidosis is typically focused on symptom management. Although tafamidis has been shown to delay neurologic progression of transthyretin familial amyloid polyneuropathy, there are no approved pharmacologic therapies shown to improve survival in TTR-CM. The natural history of TTR-CM is poorly characterized, which presents difficulties for the design of large-scale trials for new treatments. This review provides a brief overview of TTR-CM and the challenges of identifying clinically meaningful end points and study parameters to determine the efficacy of treatments for rare diseases. The design and rationale behind the ongoing phase 3 ATTR-ACT study (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial), an international, multicenter, double-blind, placebo-controlled, randomized clinical trial, is also outlined. The ATTR-ACT study will provide important insight into the efficacy and safety of tafamidis for the treatment of TTR-CM. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01994889.

Tafamidis delays neurological progression comparably across Val30Met and non-Val30Met genotypes in transthyretin familial amyloid polyneuropathy

To better characterize the effects of tafamidis in non‐Val30Met patients with transthyretin familial amyloid polyneuropathy, this post hoc analysis compared the neurological results from a 12‐month, open‐label study of non‐Val30Met versus Val30Met patients at month 12 from the 18‐month, double‐blind, placebo‐controlled registration study. A baseline covariate adjusted analysis was used to control for differences in baseline neurological severity.

Practice patterns of ophthalmologists administering intravitreal injections in Europe: a longitudinal survey

Purpose This study was performed to understand the practice patterns of ophthalmologists administering intravitreal (IVT) injections in Europe after the procedure became routine. Methods As part of a prospective, multinational, non-interventional cohort study in 13 countries in Europe between 2006 and 2012, ophthalmologists completed the Baseline Questionnaire and the Follow-up Questionnaire 1 year after baseline. Results and discussion Of the 125 ophthalmologists who participated in the study, 113 (90.4%) completed the Baseline Questionnaire. Most of these ophthalmologists were medical retina specialists (43.0%). The median number of IVT injections that the ophthalmologists performed per month during the year prior to completing the Baseline Questionnaire was 20.0. The majority of the ophthalmologists had performed their last IVT injection prior to completing the questionnaire in an operating room or theater (68.4%). When performing IVT injections, a majority of the ophthalmologists reported applying povidone–iodine (90.4%) before IVT injections and topical antibiotics right after IVT injections (89.5%). In addition, 81.6% of the ophthalmologists reported using a sterile adhesive eye drape and 80.7% reported using an eyelid speculum. In all, 95 ophthalmologists (76%) completed the Follow-up Questionnaire. The median number of IVT injections performed per month during the year prior to completing the Follow-up Questionnaire by these ophthalmologists was increased to 35. The results of the Follow-up Questionnaire on administering IVT injections were similar to those of the Baseline Questionnaire. A majority of the ophthalmologists reported applying povidone–iodine (87.4%) before IVT injections, topical antibiotics right after IVT injections (89.5%), and an eyelid speculum (85.3%). Conclusion The results of this study indicated a good adherence to all aspects of the guidelines on IVT injections. It seemed that ophthalmologists were more experienced in IVT injections after they became a routine treatment procedure.

A retrospective, pooled data analysis of the safety of pegaptanib sodium in the treatment of age-related macular degeneration in subjects with or without diabetes mellitus

BackgroundTo evaluate the safety of pegaptanib sodium 0.3 mg intravitreal injection in the treatment of neovascular age-related macular degeneration in subjects with or without diabetes mellitus.MethodsA pooled, retrospective, analysis was conducted of data from 9 sponsor-administered, randomized, open-label trials. Subjects who received pegaptanib by randomization or change in dose assignment, crossover design, or protocol amendment, were included. Reports of endophthalmitis, increased intraocular pressure, retinal injury, intraocular hemorrhage, traumatic cataract, hypersensitivity reactions, stroke, myocardial infarction, and other arterial thromboembolic events defined by the Antiplatelet Trialists’ Collaboration were identified by Medical Dictionary for Regulatory Activities preferred terms. Adverse events were summarized from the first injection to 42 days after the last injection. The incidence of adverse events was stratified by the presence/absence of diabetes.ResultsOf 1,586 subjects enrolled, 165 (10.4%) had a history of diabetes mellitus and 1,421 (89.6%) did not. The 2 populations were similar at baseline. Based on the comparison of prespecified ocular, hypersensitivity, and Antiplatelet Trialists’ Collaboration event terms, the safety review did not identify any notable differences between the 2 populations.ConclusionsThis retrospective analysis found no increased safety risk resulting from treatment with pegaptanib 0.3 mg in individuals with neovascular age-related macular degeneration and concomitant diabetes mellitus.