Factors Linked to Injection Interval Extension in Eyes with Wet Age-Related Macular Degeneration Switched to Brolucizumab.

PURPOSE: To evaluate factors associated with anti-vascular endothelial growth factor (VEGF) injection interval extension in patients with neovascular age-related macular degeneration (nAMD) switched to brolucizumab treatment. DESIGN: Retrospective, observational cohort study. PARTICIPANTS: Adults in the United States-based IRIS® Registry (Intelligent Research in Sight) with nAMD who switched from another anti-VEGF agent to brolucizumab-only treatment for ≥ 12 months from October 8, 2019, through November 26, 2021. METHODS: Univariable and multivariable analyses examined associations of demographic and clinical characteristics with the likelihood of interval extension after switching to brolucizumab therapy. MAIN OUTCOME MEASURES: Eyes were classified as either extenders or nonextenders at 12 months. Extenders were eyes that achieved (1) an extension of ≥ 2 weeks in the brolucizumab injection interval at 12 months versus the interval before switching (time between the last known prior anti-VEGF injection and first [index] brolucizumab injection) and (2) stable (< 10 letters gained or lost) or improved (≥ 10 letters gained) visual acuity (VA) at 12 months versus VA at index injection. RESULTS: Of 2015 eyes among 1890 patients who switched to brolucizumab treatment, 1186 (58.9%) were extenders. In univariable analyses, demographic and clinical characteristics were comparable between extenders and nonextenders, except that extenders had shorter intervals before switching versus nonextenders (mean, 5.9 ± 2.1 weeks vs. 10.1 ± 7.6 weeks, respectively). In multivariable logistic regression modeling, a shorter interval before switching was associated significantly and positively with interval extension with brolucizumab therapy (adjusted odds ratio, 5.6 for interval before switching of < 8 weeks versus ≥ 8 weeks; 95% confidence interval, 4.5-6.9; P < 0.001), and eyes with an index VA of 40 to 65 letters were significantly less likely to be extenders than eyes in the higher (better) index VA categories. CONCLUSIONS: Length of the treatment interval before switching was the characteristic associated most strongly with successful interval extension with brolucizumab. Treatment-experienced patients who required more frequent injections (i.e., shorter intervals before switching) showed the greatest extensions when switching to brolucizumab. With careful consideration of benefits and risks, brolucizumab may be a valuable option for patients with higher treatment burdens because of the need for frequent injections. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

One-Year Brolucizumab Outcomes in Neovascular Age-Related Macular Degeneration from a Large United States Cohort in the IRIS® Registry.

PURPOSE: To evaluate visual acuity (VA) and injection intervals in patients with neovascular age-related macular degeneration (nAMD) after 12 months of brolucizumab therapy in clinical practice. DESIGN: Retrospective cohort study. PARTICIPANTS: Adults in the United States-based IRIS® Registry (Intelligent Research in Sight) with nAMD who received brolucizumab exclusively for 12 months (2308 eyes of 2079 patients). METHODS: Observational study of eyes with a first injection of brolucizumab (index), followed by 2 or more brolucizumab injections over the following 12 months without switching to another anti-vascular endothelial growth factor (VEGF) agent. MAIN OUTCOME MEASURES: Primary outcomes were change in best recorded VA and, for eyes receiving prior anti-VEGF therapy (treatment-experienced eyes), the difference between the brolucizumab injection interval at 12 months and the anti-VEGF injection interval before switching. The interval before switching was defined as the time between the prior anti-VEGF and index brolucizumab injections; brolucizumab interval was the time between the closest injection to day 365 and the preceding injection. Secondary outcomes included incident adverse events. RESULTS: Overall VA at index was 61.6 ± 18.4 Early Treatment Diabetic Retinopathy Study letters; 83.7% of treatment-naive eyes (184/220) and 86.1% of treatment-experienced eyes (1797/2088) showed stable (< 10 letters gained or lost) or improved (≥ 10 letters gained) VA at 12 months. Among treatment-experienced eyes receiving a prior anti-VEGF injection within 365 days before index, 29.5% (594/2015) showed an interval before switching of 8 weeks or more (mean, 7.6 ± 5.5 weeks), whereas 83.1% (1734/2015) showed a brolucizumab injection interval at 12 months of 8 weeks or more (mean, 10.3 ± 4.0 weeks). In all, 77.1% of treatment-experienced eyes (1554/2015) showed an interval extension of 1 week or more; of these, 55.4% (861/1554) showed an extension of 4 weeks or more. CONCLUSIONS: In this community-based study, at 12 months, brolucizumab treatment prolonged the interval between anti-VEGF injections for most treatment-experienced eyes, particularly those with shorter intervals before switching, while maintaining or improving VA. With careful balancing of the benefits and risks, switching to brolucizumab treatment may offer the advantage of extending the treatment interval for patients with a high anti-VEGF therapy burden. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

RETINAL VASCULITIS OR VASCULAR OCCLUSION AFTER BROLUCIZUMAB FOR NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Systematic Review of Real-World Evidence.

PURPOSE: Retinal vasculitis or vascular occlusion (RV/RO) have been reported after brolucizumab for neovascular age-related macular degeneration. This systematic literature review evaluated RV/RO events after brolucizumab in real-world practice. METHODS: Systematic literature searches identified 89 publications; 19 were included. RESULTS: Publications described 63 patients (70 eyes) with an RV/RO event following brolucizumab. Mean age was 77.6 years and 77.8% of patients were women; 32 eyes (45.7%) received one brolucizumab injection before RV/RO. Mean (range) time to event from last brolucizumab injection was 19.4 (0-63) days, with 87.5% of events occurring within 30 days. Among eyes with preevent and postevent visual acuity (VA) assessments, 22/42 eyes (52.4%) showed unchanged (±0.08 logMAR) or improved vision from last recorded preevent assessment at latest follow-up, whereas 15/42 eyes (35.7%) showed ≥0.30 logMAR (≥15 letters) VA reduction. Patients with no VA loss were on average slightly younger and had a higher proportion of nonocclusive events. CONCLUSION: Most RV/RO events reported after brolucizumab in early real-world practice occurred in women. Among eyes with VA measurements, approximately half experienced VA loss; overall, about one-third had VA reduction of ≥0.30 logMAR at latest follow-up, with indications of regional variations.

Impact of COVID-19 measures on exacerbation rates and healthcare visits in US asthma patients.

Objective: To compare exacerbation rates and healthcare resource utilization (HCRU) in real-world patients in the United States who had moderate-to-severe asthma on medium- or high-dose inhaled corticosteroid/long-acting ß2-agonist therapy at different stages before and after the pandemic. Methods: This noninterventional, retrospective study described demographics, exacerbations, HCRU, and medication use in patients from a US-wide healthcare claims database in 4 consecutive years anchored around March 15, 2020 (start date of the first emergency health measures against coronavirus disease 2019 [COVID-19], or the first lockdown, in the United States, termed "restriction onset" hereafter). Four cohorts of patients potentially eligible for moderate-to-severe asthma clinical trials at the beginning (index) of each of four 1-year periods (March 15, 2018, 2019, 2020, 2021, respectively) were built. Exacerbations, healthcare visits, and asthma medication use were counted in the 1-year period after the index for each cohort. Results: The prevalence of patients with one or more exacerbation per year decreased by 10.00% in the first year after the restriction onset compared with the year before and attenuated over time to 6.37% in the second year. The proportion of inpatient, emergency department, and physician's office visits remained stable over the time periods evaluated for all patients and those patients who experienced one or more exacerbations. Asthma treatment of patients who experienced one or more exacerbations also remained stable over the 4 years. Conclusion: The effect of COVID-19 public health measures on asthma exacerbation rates might have affected clinical trials being run during this period and should be considered in their analysis. Asthma clinical trials run under pandemic hygiene restrictions should consider lower exacerbation frequency in their study design, while treatment and healthcare visits seem unchanged.

Secukinumab's effect on structural damage progression in psoriatic arthritis: longitudinal mixture modelling of FUTURE-1 and FUTURE-5.

OBJECTIVES: Peripheral and axial manifestations of psoriatic arthritis (PsA) can lead to irreversible structural damage and chronic disability. Our objective was to explore predictors of radiographic progression and to increase our understanding of treatment effects in subgroups of patients with different rates of structural damage progression. METHODS: We analysed data from two large Phase-3 trials of secukinumab in PsA patients, FUTURE-1 (NCT01392326, n=606) and FUTURE-5 (NCT02404350, n=996), where different posologies ranging from 75 mg to 300 mg were used. We applied a longitudinal Bayesian mixture model with random effects to account for the variability in the repeated radiographic assessments. "Fast progressors" were defined post hoc as patients with a 50% model-estimated probability to progress at least 0.5 mTSS/year faster than an average patient. RESULTS: Higher baseline inflammation and higher body weight were identified as significant predictors of radiographic progression (multivariate model). Model-estimated structural damage progression in an average patient treated with secukinumab 150 mg subcutaneous (s.c.) was slower (0.04 mTSS/year; 95% CI -0.28, 0.34) compared to a patient treated with placebo (0.94 mTSS/year; 95% CI 0.45, 1.45). According to the model, the subgroup of "fast progressors" (hsCRP ≥26 mg/L, body weigth ≥94 kg, inadequate response to prior anti-TNF-alpha, structural damage ≥42 mTSS) treated with secukinumab 150 mg s.c. progressed at 0.56 mTSS/year (95% CI 0.02, 1.09) and 1.46 mTSS/year (95% CI 0.81, 2.11) when treated with placebo. CONCLUSIONS: Greater systemic inflammation and higher body weight at baseline were identified as significant predictors of progression. Even patients with fast radiographic progression could experience a beneficial effect with secukinumab that holds promise to prevent further mobility loss.

The "RCT augmentation": a novel simulation method to add patient heterogeneity into phase III trials.

BACKGROUND: Phase III randomized controlled trials (RCT) typically exclude certain patient subgroups, thereby potentially jeopardizing estimation of a drug's effects when prescribed to wider populations and under routine care ("effectiveness"). Conversely, enrolling heterogeneous populations in RCTs can increase endpoint variability and compromise detection of a drug's effect. We developed the "RCT augmentation" method to quantitatively support RCT design in the identification of exclusion criteria to relax to address both of these considerations. In the present manuscript, we describe the method and a case study in schizophrenia. METHODS: We applied typical RCT exclusion criteria in a real-world dataset (cohort) of schizophrenia patients to define the "RCT population" subgroup, and assessed the impact of re-including each of the following patient subgroups: (1) illness duration 1-3 years; (2) suicide attempt; (3) alcohol abuse; (4) substance abuse; and (5) private practice management. Predictive models were built using data from different "augmented RCT populations" (i.e., subgroups where patients with one or two of such characteristics were re-included) to estimate the absolute effectiveness of the two most prevalent antipsychotics against real-world results from the entire cohort. Concurrently, the impact on RCT results of relaxing exclusion criteria was evaluated by calculating the comparative efficacy of those two antipsychotics in virtual RCTs drawing on different "augmented RCT populations". RESULTS: Data from the "RCT population", which was defined with typical exclusion criteria, allowed for a prediction of effectiveness with a bias < 2% and mean squared error (MSE) = 5.8-6.8%. Compared to this typical RCT, RCTs using augmented populations provided improved effectiveness predictions (bias < 2%, MSE = 5.3-6.7%), while returning more variable comparative effects. The impact of augmentation depended on the exclusion criterion relaxed. Furthermore, half of the benefit of relaxing each criterion was gained from re-including the first 10-20% of patients with the corresponding real-world characteristic. CONCLUSIONS: Simulating the inclusion of real-world subpopulations into an RCT before running it allows for quantification of the impact of each re-inclusion upon effect detection (statistical power) and generalizability of trial results, thereby explicating this trade-off and enabling a controlled increase in population heterogeneity in the RCT design.

The "Efficacy-Effectiveness Gap": Historical Background and Current Conceptualization.

BACKGROUND: The concept of the "efficacy-effectiveness gap" (EEG) has started to challenge confidence in decisions made for drugs when based on randomized controlled trials alone. Launched by the Innovative Medicines Initiative, the GetReal project aims to improve understanding of how to reconcile evidence to support efficacy and effectiveness and at proposing operational solutions. OBJECTIVES: The objectives of the present narrative review were 1) to understand the historical background in which the concept of the EEG has emerged and 2) to describe the conceptualization of EEG. METHODS: A focused literature review was conducted across the gray literature and articles published in English reporting insights on the EEG concept. The identification of different "paradigms" was performed by simple inductive analysis of the documents' content. RESULTS: The literature on the EEG falls into three major paradigms, in which EEG is related to 1) real-life characteristics of the health care system; 2) the method used to measure the drug's effect; and 3) a complex interaction between the drug's biological effect and contextual factors. CONCLUSIONS: The third paradigm provides an opportunity to look beyond any dichotomy between "standardized" versus "real-life" characteristics of the health care system and study designs. Namely, future research will determine whether the identification of these contextual factors can help to best design randomized controlled trials that provide better estimates of drugs' effectiveness.

Real-World Safety Outcomes with Brolucizumab in Neovascular Age-Related Macular Degeneration: Findings from the IRIS® Registry.

INTRODUCTION: To assess real-world safety outcomes for adults with neovascular age-related macular degeneration (nAMD) treated with brolucizumab from the US-based IRIS® (Intelligent Research in Sight) Registry. METHODS: In this retrospective study, 18,312 eyes (15,998 patients) treated with ≥ 1 intravitreal brolucizumab injections between 8 October 2019 (US launch date for brolucizumab) and 7 October 2021 were followed up for ≤ 2 years after first injection (index date). The study assessed the predefined incident ocular adverse events of intraocular inflammation (IOI), retinal vasculitis (RV), and retinal vascular occlusion (RO). RESULTS: Overall, 614/18,312 eyes (3.4%) experienced any IOI, RV, and/or RO event. Median (interquartile range [IQR]) time to an event was 84 (42-167) days; 77.4% of events (475/614) occurred within 6 months after index date. Median (IQR) number of brolucizumab injections before an event was 2 (1-4). For eyes with an adverse event and visual acuity (VA) data (n = 406), median (IQR) change in Early Treatment of Diabetic Retinopathy Study (ETDRS) letters from pre-event VA was 0 (- 7 to + 5) at the 6-month follow-up; 50 eyes (12.3%) had a VA loss of 10 or more ETDRS letters. Risk of an event (hazard ratio [95% confidence interval]) was decreased in eyes from male patients (0.61 [0.53-0.71]), from older patients (0.83 [0.76-0.90]), from treatment-naive patients (0.51 [0.38-0.69]), and from patients who started brolucizumab in the second year after launch (0.68 [0.53-0.86] vs. first year). CONCLUSION: In this large real-world brolucizumab safety study, 3.4% of eyes experienced an IOI, RV, and/or RO event. Among eyes that experienced an adverse event for which VA data were available, median ETDRS vision change was 0 letters (IQR - 7 to + 5).

Multimorbidities in COPD are Associated With Increased Exacerbations and Health Care Resource Utilization in Real-World Patients from a U.S. Database.

Background: Patients with COPD often develop other morbidities, suggesting a systemic component to this disease. This retrospective non-interventional cohort study investigated relationships between multimorbidities in COPD and their impact on COPD exacerbations and COPD-related healthcare resource utilization (HCRU) using real-world evidence from Optum's de-identified Clinformatics® Data Mart Database. Methods: Demographic and clinical characteristics were assessed. Overall comorbidity burden and proportion of individuals with gastroesophageal reflux disease (GERD), diabetes or osteoporosis/osteopenia were compared in age-matched COPD versus non-COPD cohorts using descriptive statistics. COPD exacerbations and COPD-related HCRU (hospitalizations and emergency room visits) were compared between age-matched cohorts of COPD patients with and without specific common morbidities (GERD, diabetes and osteoporosis/osteopenia). Additional weight-matching was performed for matched cohorts of COPD patients with and without diabetes, and with and without osteoporosis/osteopenia. Follow-up period was five years. Results: Age-matched cohorts with and without COPD each comprised 158,106 patients. Morbidities were more common in the COPD cohort than the cohort without COPD (GERD: 44.9% vs 27.8%; diabetes: 40.8% vs 31.1%; osteoporosis/osteopenia: 18.8% vs 14.1%, respectively). Compared with matched cohorts with COPD only, cohorts of COPD patients with either GERD, diabetes or osteoporosis/osteopenia, experienced increased risk of severe exacerbations (odds ratio [OR]=1.819, OR=1.119 and OR=1.373, respectively), moderate exacerbations (OR=1.699, OR=1.102 and OR=1.322, respectively) or any exacerbations OR=1.848, OR=1.099 and OR=1.384, respectively, p<0.001 for all comparisons and increased risk of COPD-related HCRU (ER visits: OR=1.983, OR=1.098 and OR=1.343, respectively; Hospitalization visits: OR=2.222, OR=1.26 and OR=1.368, respectively; p<0.001 for all comparisons). Conclusion: These real-world data confirm that GERD, diabetes, and osteoporosis are common morbidities in patients with COPD and, moreover, that they affect frequency of exacerbation and HCRU. Determining and addressing the mechanisms behind the systemic effects of COPD may be beneficial for COPD patients and may also help reduce COPD exacerbations.

The Treatment Patterns with Brolucizumab in Germany (REALIZE) Study: A Retrospective Cohort Study Based on Longitudinal Prescription Data.

INTRODUCTION: This study describes real-world treatment patterns in Germany for brolucizumab, an anti-vascular endothelial growth factor (anti-VEGF) therapy for neovascular age-related macular degeneration (nAMD). METHODS: This single-arm retrospective cohort study used German patient-level prescription data. Patients aged ≥ 50 years, who received ≥ 1 brolucizumab prescription in one eye only (unilateral) and had a minimum of 12 months follow-up were included. Three cohorts were defined from the overall population: anti-VEGF treatment-naive patients ("treatment-naive"); anti-VEGF treatment-experienced patients ("treatment-experienced"); and of the treatment-experienced cohort, patients persistent on brolucizumab for 12 months ("treatment-experienced persistent"), i.e. who received ≥ 2 brolucizumab injections and did not discontinue or use other anti-VEGF agents in that period. Descriptive statistics were used to analyse patient characteristics and injection intervals. RESULTS: A total of 2089 patients with at least 12 months follow-up and one brolucizumab injection were analysed. Most were female (58.1%), aged 80+ years (54.7%). A total of 539 (25.8%) were treatment-naive, 1550 (74.2%) treatment-experienced and, of those, 787 (50.8%) were persistent. Overall, the median (interquartile range, IQR) number of brolucizumab injections during the 12 months follow-up was 5.0 (3.0-8.0). In the treatment-naive and treatment-experienced sub-cohorts it was 5.0 (3.0-8.0) and 5.0 (3.0-9.0) injections, respectively. In the treatment-experienced persistent cohort the median (IQR) number of injections was 8.0 (5.0-10.0). In this same cohort, the median (IQR) treatment interval between anti-VEGF injections before switch to brolucizumab was 5.1 (4.0-8.0) weeks, whilst the brolucizumab interval at 12 months after switch was 8.0 (6.0-11.9) weeks. Of treatment-experienced patients, 67% extended their treatment interval and those with pre-switch intervals less than 6 weeks (< q6w), in particular, had meaningful treatment interval extensions. CONCLUSION: Patients who switched to brolucizumab had a median treatment interval extension of about 3 weeks at 12 months. These results show that treatment with brolucizumab has the potential to reduce treatment burden in patients with nAMD in routine clinical practice.

Real-World Persistence and Treatment Interval in Patients with Diabetic Macular Edema Treated with Anti-Vascular Endothelial Growth Factors in the USA.

INTRODUCTION: There is little understanding of long-term treatment persistence in patients receiving anti-vascular endothelial growth factor (anti-VEGF) injections for diabetic macular edema (DME), particularly relating to treatment intervals. The aim of this study was to investigate the association between treatment interval and discontinuation rate after 24 months of unilateral anti-VEGF treatment in patients with DME under routine clinical care in the USA. METHODS: This was a non-interventional, retrospective cohort study to review the health insurance claims of adults with DME linked with the IBM MarketScan® Commercial and Medicare Supplemental databases, who were continuously enrolled in a health plan for at least 6 months prior to their first anti-VEGF treatment and for a duration of at least 24 months between July 2011 and June 2017. Patients were grouped on the basis of the injection interval they achieved at 24 months of treatment. Discontinuation rate beyond 24 months and its association with treatment intervals at 24 months was estimated using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: The overall discontinuation rate among the 1702 eligible patients from 24 to 60 months after treatment initiation was 30%. At 60 months, patients were more likely to remain on treatment in shorter (75.3% [4-week interval group]) versus longer treatment interval groups (62.1% [> 12-week interval group], difference = 13.2%, [95% confidence interval (CI) 1.06, 2.06], p = 0.01). Patients on a > 12-week interval were twice as likely to discontinue treatment compared with those on an 8-week interval (hazard ratio = 2.01 [95% CI 1.43, 2.82], p < 0.001). CONCLUSION: Patients with DME on longer anti-VEGF treatment intervals at 24 months consistently had higher discontinuation rates in the following years than those on shorter treatment intervals.

Short-Term Treatment Outcomes of Brolucizumab in Patients with Neovascular Age-Related Macular Degeneration: A Multicentre Indian Real-World Evidence Study.

Objective: To evaluate the short-term effectiveness and safety outcomes following brolucizumab treatment in patients with neovascular age-related macular degeneration (nAMD) as a part of real-world clinical practice in India. Methods: This was a retrospective, observational, multicentre study including patients (≥50 years old) diagnosed with nAMD. Anonymized data of the patients receiving the first dose of brolucizumab intravitreal injection (IVI) who were either treatment-naïve or previously treated with a single or a combination of other anti-VEGF IVIs were included. The present study reported the change in retinal fluid levels from baseline to month 3, best-corrected visual acuity (BCVA), central retinal thickness (CRT), and the number of injections received. The adverse events in the three months after brolucizumab treatment initiation were also monitored. Results: The study included 63 patients (65 eyes) from four study centres across India (mean age: 69.1 ± 9.7 years). A total of 82 brolucizumab injections were administered during the 3 months of study duration, with 52/65 (80.0%) eyes receiving only 1 injection. Resolution of IRF, SRF, and PED was observed in 76.9%, 64.6%, and 67.7% of eyes, respectively. Further, a significant reduction in CRT was observed (baseline: 403.5 ± 118.7 µm; month 3: 308.3 ± 73.8 µm; p < 0.001), and BCVA also improved notably from 0.7 ± 0.5 logMAR at baseline to 0.5 ± 0.4 logMAR at month 3 (p < 0.001). Adverse events (AEs) were reported in 3 eyes from 3 patients; retinal pigment epithelial rip (1) and subretinal hemorrhage (2) after the first injection of brolucizumab, however, none discontinued the treatment. Conclusion: The study reports on the short-term effectiveness and tolerability of brolucizumab therapy in the management of nAMD in both treatment-naïve and switch eyes. Brolucizumab was observed to have a favourable benefit-risk profile, and study results were within the known safety profile, with no instances of intraocular inflammation.

Testing the "RCT augmentation" methodology: A trial simulation study to guide the broadening of trials eligibility criteria and inform on effectiveness.

Background: Exclusion criteria that are treatment effect modifiers (TEM) decrease RCTs results generalisability and the potentials of effectiveness estimation. In "augmented RCTs", a small proportion of otherwise-excluded patients are included to allow for effectiveness estimation. In Hodgkin Lymphoma (HL) RCTs, older age and comorbidity are common exclusion criteria, while also TEM. We simulated HL RCTs augmented with age or comorbidity, and explored in each scenario the impact of augmentation on effectiveness estimation accuracy. Methods: Simulated data with a population of HL individuals initiating drug A or B was generated. There were drug-age and drug-comorbidity interactions in the simulated data, with a greater magnitude of the former compared to the latter. Multiple augmented RCTs were simulated by randomly selecting patients with increasing proportions of older, or comorbid patients. Treatment effect size was expressed using the between-group Restricted Mean Survival Time (RMST) difference at 3 years. For each augmentation proportion, a model estimating the "real-world" treatment effect (effectiveness) was fitted and the estimation error measured (Root Mean Square Error, RMSE). Results: In simulated RCTs including none (0%), or the real-world proportion (30%) of older patients, the interquartile range of RMST difference was 0.4-0.5 years and 0.2-0.3 years, respectively, and RMSE were 0.198 years (highest possible error) and 0.056 years (lowest), respectively. Augmenting RCTs with 5% older patients decreased estimation error substantially (RMSE = 0.076 years). Augmentation with comorbid patients proved less useful for effectiveness estimation. Conclusion: In augmented RCTs aiming to inform the effectiveness of drugs, augmentation should concern in priority those exclusion criteria of suspected important TEM magnitude, so as to minimie the proportion of augmentation necessary for good effectiveness estimations.

Efficacy and safety of brolucizumab in age-related macular degeneration: A systematic review of real-world studies.

Intravitreally injected anti-vascular endothelial growth factor (anti-VEGF) agents are first-line treatment for neovascular age-related macular degeneration (nAMD). Phase 3 trials demonstrated non-inferiority of anti-VEGF therapy with brolucizumab compared with aflibercept in best corrected visual acuity (BCVA) gains, with superior anatomical outcomes after brolucizumab. The purpose of the review was to summarize real-world efficacy and safety data on brolucizumab in patients with nAMD. The review protocol was registered with PROSPERO (ID: CRD42021290530). We conducted systematic searches in Embase, Medline and key ophthalmology congress websites (19 October 2021). Original reports of efficacy and/or safety in patients receiving brolucizumab to treat nAMD in clinical practice were eligible. The descriptive summary includes reports describing at least 10 brolucizumab-treated eyes. In total, 2907 brolucizumab-treated eyes from 26 studies were included. Outcomes were available for treatment-naive eyes (six studies), eyes switched to brolucizumab from other anti-VEGFs (16 studies), and/or treatment-naive and switch eyes combined (eight studies). Follow-up time points ranged from 4 weeks to 1 year post-brolucizumab initiation. For BCVA, significant improvements compared with brolucizumab initiation were reported in four of six studies in treatment-naive eyes (mean BCVA improvement, range: +3.7 to +11.9 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) and in three of 12 studies in switch eyes (range: +9.0 to +15 ETDRS letters) (all p < 0.05); remaining studies reported no significant post-brolucizumab BCVA changes. For central subfield thickness (CST), improvements post-brolucizumab initiation were reported in all six studies in treatment-naive eyes (mean CST improvement, range: -113.4 to -150.1 µm) and in eight of 11 studies in switch eyes (range: -26 to -185.7 µm) (all p < 0.05). The 14 studies reporting on intraretinal, subretinal and/or total fluid observed improvements post-brolucizumab initiation. The four studies comparing treatment intervals observed extension of the interval between injections after switching to brolucizumab from other anti-VEGFs. Incidence of intraocular inflammation ranged from 0% to 19%. In conclusion, real-world efficacy and safety data concur with brolucizumab pivotal trials. Additionally, reduction of disease activity in anti-VEGF switch eyes was demonstrated by fluid reduction and/or visual acuity gain, along with prolongation of the interval between injections.

Real-World Frequency and Management of Ocular Adverse Events in Eyes with Neovascular Age-Related Macular Degeneration Treated with Brolucizumab.

INTRODUCTION: Intraocular inflammation (IOI)-related adverse events (AEs) that may result in severe vision loss have been associated with the anti-vascular endothelial growth factor brolucizumab. In this study, we investigate the timing, management and resolution of IOI-related AEs in a large cohort of patients treated with at least one injection of brolucizumab in routine clinical practice. METHODS: Retrospective review of medical records from patients with neovascular age-related macular degeneration treated with ≥ 1 brolucizumab injection between October 2019 and November 2021 at the Retina Associates of Cleveland, Inc. clinics. RESULTS: Of the 482 eyes included in the study, IOI-related AEs occurred in 22 (4.6%) eyes. Four (0.8%) eyes developed retinal vasculitis (RV) and of these, 2 (0.4%) had concomitant retinal vascular occlusion (RO). Most eyes [14/22 (64%)] developed the AE within 3 months and 4/22 (18%) within 3-6 months of the first brolucizumab injection. The median [interquartile range (IQR)] time from the last brolucizumab injection to development of the IOI-related AE was 13 (4-34) days. At the time of event, 3 (0.6%) eyes with IOI (no RV/RO) developed severe vision loss of ≥ 30 ETDRS letters, and a further 5 (1.0%) eyes (1 with IOI + RV, 1 with IOI + RV + RO) developed moderate vision loss of ≥ 15 letters compared with their last visual acuity (VA) prior to the AE. The median (IQR) vision loss was -6.8 (-19.9, -0.0) letters. Taking the best VA at either 3 or 6 months after AE resolution (or stability for occlusive events), VA decreased by ≥ 5 letters compared with prior to the AE in 3 (14%) of the 22 affected eyes, and was preserved (< 5-letter loss) in 18 (82%) eyes. CONCLUSIONS: In this real-world study, most IOI-related AEs occurred early after brolucizumab treatment initiation. With appropriate monitoring and management of IOI-related AEs, vision loss associated with brolucizumab may be limited.

Handling Missing Data in Health Economics and Outcomes Research (HEOR): A Systematic Review and Practical Recommendations.

BACKGROUND: Missing data in costs and/or health outcomes and in confounding variables can create bias in the inference of health economics and outcomes research studies, which in turn can lead to inappropriate policies. Most of the literature focuses on handling missing data in randomized controlled trials, which are not necessarily always the data used in health economics and outcomes research. OBJECTIVES: We aimed to provide an overview on missing data issues and how to address incomplete data and report the findings of a systematic literature review of methods used to deal with missing data in health economics and outcomes research studies that focused on cost, utility, and patient-reported outcomes. METHODS: A systematic search of papers published in English language until the end of the year 2020 was carried out in PubMed. Studies using statistical methods to handle missing data for analyses of cost, utility, or patient-reported outcome data were included, as were reviews and guidance papers on handling missing data for those outcomes. The data extraction was conducted with a focus on the context of the study, the type of missing data, and the methods used to tackle missing data. RESULTS: From 1433 identified records, 40 papers were included. Thirteen studies were economic evaluations. Thirty studies used multiple imputation with 17 studies using multiple imputation by chained equation, while 15 studies used a complete-case analysis. Seventeen studies addressed missing cost data and 23 studies dealt with missing outcome data. Eleven studies reported a single method while 20 studies used multiple methods to address missing data. CONCLUSIONS: Several health economics and outcomes research studies did not offer a justification of their approach of handling missing data and some used only a single method without a sensitivity analysis. This systematic literature review highlights the importance of considering the missingness mechanism and including sensitivity analyses when planning, analyzing, and reporting health economics and outcomes research studies.

Switching to brolucizumab: injection intervals and visual, anatomical and safety outcomes at 12 and 18 months in real-world eyes with neovascular age-related macular degeneration.

BACKGROUND: The anti-vascular endothelial growth factor (anti-VEGF) injection interval influences treatment burden and compliance in neovascular age-related macular degeneration (nAMD). This real-world study investigates visual acuity (VA), injection-interval extension, central macular thickness (CMT) and safety in nAMD eyes switched to the anti-VEGF agent brolucizumab and followed for up to 18 months. METHODS: This retrospective study included patients with nAMD who were switched from other anti-VEGF agents to brolucizumab only. Patient eyes were grouped into three nested cohorts with the overall cohort receiving ≥ 1 brolucizumab injection, the second receiving ≥ 3 brolucizumab injections with a follow-up period of ≥ 12 months and the third cohort receiving ≥ 3 brolucizumab injections with a follow-up period of ≥ 18 months. Study endpoints included changes from baseline at 12 or 18 months in VA, injection intervals, and CMT. Sub-group analyses were conducted using baseline injection interval length or baseline VA as qualifiers. RESULTS: Overall, 482 eyes received ≥ 1 brolucizumab injection; 174 eyes received ≥ 3 brolucizumab injections with ≥ 12 months of follow-up, and 95 eyes received ≥ 3 brolucizumab injections with ≥ 18 months of follow-up. VA (mean [95% confidence intervals]) remained stable relative to baseline after 12 months (- 1.1 [- 3.7, 1.6] letters; p = 0.42) and 18 months (0.0 [- 3.1, 3.1] letters; p = 0.98) of brolucizumab treatment, respectively, and pre-switch injection intervals or baseline VA had no notable effect. Following the switch to brolucizumab, injection intervals were extended from baseline to month 12 by 26.9 (19.7, 34.0) days (p < 0.0001), and eyes with pre-switch injection intervals < 8 weeks were able to have their injection intervals extended by 23.6 days longer than eyes with pre-switch injection intervals ≥ 8 weeks. At 18 months, injection intervals were extended by 36.3 (25.6, 46.9) days (p < 0.0001) compared to baseline. Following switch to brolucizumab, CMT was reduced at both 12 and 18 months (12 months: - 35.2 (- 51.7, - 18.8) µm, p < 0.0001; 18 months: - 38.9 (- 54.3, - 22.0) µm, p < 0.0001). Intraocular inflammation-related adverse events were reported in 4.6% of brolucizumab-treated eyes. CONCLUSIONS: This real-world study demonstrates that injection intervals may be significantly extended with maintained vision and reduced CMT in nAMD eyes switching to brolucizumab therapy from other anti-VEGFs.

One-Year and 18-Month Outcomes in nAMD Patient Eyes Switched to Brolucizumab Alone versus to Brolucizumab Alternating with Other Anti-VEGF Agents.

Objective: Retrospective, real-world study to evaluate visual acuity (VA), anti-vascular endothelial growth factor (anti-VEGF) injection intervals, and central macular thickness (CMT) in neovascular age-related macular degeneration (nAMD) eyes switched to brolucizumab only or to brolucizumab alternating with another anti-VEGF. Methods: The overall study population comprised eyes that were given ≥1 brolucizumab injection between 1 October 2019 and 30 November 2021. The brolucizumab-only (BRO) cohort consisted of prior anti-VEGF-treated eyes treated exclusively with ≥3 brolucizumab injections over ≥12 or ≥18 months; the alternating brolucizumab (ALT) cohort comprised prior anti-VEGF-treated eyes treated with ≥2 brolucizumab injections and ≥1 other anti-VEGF over ≥12 or ≥18 months. Results: A total of 482 eyes received ≥1 brolucizumab injection during the study period. Mean VA changes from baseline were -1.1±15.1 letters (BRO cohort; n = 174) and 1.3±13.0 letters (ALT cohort; n = 47) at Month 12, and 0.0±13.5 letters (BRO cohort; n = 95) and -7.3±17.2 letters (ALT cohort; n = 29) at Month 18. Mean changes in injection intervals were +26.9±48.1 days (BRO cohort) and +11.1±17.3 days (ALT cohort) at Month 12 and +36.3±52.3 days (BRO cohort) and +14.0±19.9 days (ALT cohort) at Month 18. Mean changes in CMT were -35.2±108.1 µm (BRO cohort) and -31.5±91.2 µm (ALT cohort) at Month 12 and -38.9±75.0 µm (BRO cohort) and -9.0±59.9 µm (ALT cohort) at Month 18. Intraocular inflammation-related adverse events were recorded in 22/482 (4.6%) eyes. Conclusion: Treatment with either brolucizumab alone or brolucizumab alternating with another anti-VEGF can preserve vision, reduce CMT, and extend anti-VEGF injection intervals in patients with nAMD.

Anti-Vascular Endothelial Growth Factor Treatment Discontinuation and Interval in Neovascular Age-Related Macular Degeneration in the United States.

PURPOSE: To assess the association between treatment interval and likelihood of anti-vascular endothelial growth factor (anti-VEGF) discontinuation among patients with neovascular age-related macular degeneration (nAMD) in a real-world setting in the United States. DESIGN: Retrospective clinical cohort study. METHODS: Health insurance claims data from the IBM MarketScan Commercial and Medicare Supplemental databases were retrospectively reviewed to identify adults with nAMD who received anti-VEGF for the first time between July 1, 2011, and June 30, 2017. The proportion of discontinued patients was analyzed using Kaplan-Meier curves. Cox proportional hazards models were used to examine the association between treatment intervals at 24 months and anti-VEGF discontinuation. RESULTS: The analysis included 8167 patients on continuous, unilateral anti-VEGF treatment for at least 24 months. Baseline demographics and clinical characteristics were well balanced between treatment interval groups. The overall rate of discontinuation from 24 months until 60 months after treatment initiation was 30.4%. At 60 months, patients on shorter treatment intervals were more likely to remain on treatment than those on longer intervals, ranging from 76.8% (4-week interval group) to 60.6% (>12-week interval group) and corresponding to a 28% lower likelihood (HR [SE] 0.72 [0.12], P < .01) and 55% higher likelihood of discontinuing treatment (HR [SE] 1.55 [0.07], P < .01), respectively, compared with the 8-week group. CONCLUSIONS: nAMD patients on longer anti-VEGF treatment intervals at 24 months had consistently higher discontinuation rates than patients on shorter intervals in the following years. This highlights the need to support and educate patients on long treatment intervals to continue with their treatment.

Comparative Efficacy of Brolucizumab in the Treatment of Neovascular Age-Related Macular Degeneration: A Systematic Literature Review and Network Meta-Analysis.

INTRODUCTION: A systematic literature review (SLR) and network meta-analysis (NMA) were conducted to evaluate the comparative efficacy of brolucizumab relative to other anti-vascular endothelial growth factor (VEGF) treatments for neovascular age-related macular degeneration (nAMD) at 1 and 2 years, and overall safety and injection frequency of each treatment. METHODS: An SLR identifying randomized controlled trials (RCTs) published before June 2021 according to a pre-specified protocol was followed by a Bayesian NMA to compare brolucizumab (6 mg q12w/q8w) against sham and all relevant anti-VEGF regimens. Pooled mean injection frequency, serious adverse ocular events, and discontinuation rates were estimated for each treatment regimen. RESULTS: Nineteen RCTs were included in NMA base-case analysis. Brolucizumab (6 mg q12w/q8w) with loading-phase (LP) demonstrated superior best-corrected visual acuity (BCVA) gains to sham both at year 1 (mean difference 16.8 [95%CrI 13.3, 20.4]) and year 2 (mean difference 21.2 [95%CrI 17.4, 25.0]) and was comparable to other anti-VEGFs. Brolucizumab (6 mg q12w/q8w) also showed superior retinal thickness reduction to most comparators including ranibizumab (0.5 mg q4w; year 1 mean difference - 50.1 [95%CrI - 70.3, - 29.8]; year 2 mean difference - 49.5 [95%CrI - 70.8, - 28.6]), aflibercept (2 mg q8w; year 1 mean difference - 39.7 [95%CrI - 52.9, - 26.4]; year 2 mean difference - 35.0 [95%CrI - 49.1, - 21.4]), and faricimab (6 mg q16w/q8w; year 1 mean difference - 27.6 [95%CrI - 42.3, - 12.8]). Brolucizumab (6 mg q12w/q8w) showed similar rates of treatment discontinuation and serious and overall adverse events (both years). At year 2, pooled annualized injection frequency was lowest for brolucizumab (6 mg q12w/q8w) and highest for ranibizumab (0.5 mg q4w) at 5.7 and 11.5 injections annually, respectively. CONCLUSION: Among all licensed anti-VEGF treatments, brolucizumab showed superior reduction in retinal thickness and comparable BCVA gains and discontinuation rates, despite having the lowest injection frequency. The current study provides the most up-to-date, robust comparison of treatments for nAMD.