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Long-term outcomes with as-needed aflibercept in diabetic macular oedema: 2-year outcomes of the ENDURANCE extension study
  1. Charles C Wykoff1,2,
  2. William C Ou1,
  3. Rahul N Khurana3,4,
  4. David M Brown1,2,
  5. W Lloyd Clark5,
  6. David S Boyer6
  7. for the ENDURANCE Study Group
  1. 1 Retina Consultants of Houston, Houston, Texas, USA
  2. 2 Blanton Eye Institute, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas, USA
  3. 3 Northern California Retina Vitreous Associates, Mountain View, California, USA
  4. 4 Department of Ophthalmology, University of California, San Francisco, California, USA
  5. 5 Palmetto Retina Center, West Columbia, South Carolina, USA
  6. 6 Retina-Vitreous Associates Medical Group, Los Angeles, California, USA
  1. Correspondence to Dr Charles C Wykoff, Retina Consultants of Houston and Blanton Eye Institute, Houston Methodist Hospital and Weill Cornell Medical College, Houston, TX 77030, USA; ccwmd{at}houstonretina.com

Abstract

Background/aims To evaluate the efficacy and safety of individualised 2.0 mg intravitreal aflibercept retreatment for diabetic macular oedema (DME) through the fifth year of management.

Methods This is a phase IV, 2-year, open-label extension study. Sixty patients completing the 3-year VISTA DME (Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema) phase III trial enrolled in the ENDURANCE (Long-Term Efficacy and Safety of Intravitreal Aflibercept for the Treatment of DME in Subjects Who Completed the VISTA DME Trial) extension study. All patients received aflibercept in the presence of clinically relevant DME. Intervals between visits were prescribed according to disease activity. The main outcome measure was mean aflibercept injections given through 2 years.

Results A mean of 7.7 aflibercept injections were administered through 2 years. Fifteen (25%) patients required no retreatment and 48% (n=29) of patients received five or fewer injections through 2 years. Among patients who received at least one aflibercept retreatment during ENDURANCE, the mean number of injections through 2 years was 9.5. The mean visual acuity and central retinal thickness gains achieved during VISTA DME were maintained and stable during ENDURANCE. The most notable safety signal was progression of diabetic retinopathy. Six (10%) patients converted from non-proliferative to proliferative diabetic retinopathy (PDR), and a total of eight patients experienced PDR events occurring at a mean of 387 days following the previous aflibercept treatment.

Conclusion The need for aflibercept retreatment was substantially reduced in the fourth and fifth years of aflibercept dosing for DME following initiation of therapy in the VISTA DME trial. While vision gains achieved during the 3-year VISTA DME trial were maintained through ENDURANCE with a reduced treatment burden, clinically relevant worsening of diabetic retinopathy was observed with progression to PDR in 10% of the eyes.

Trial registration number NCT02299336

  • retina
  • treatment medical

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Introduction

Diabetes mellitus is a global epidemic with approximately 1 in 12 adults being directly affected. Microvascular damage to the retina, diabetic retinopathy (DR), is one of the most common end-organ manifestations of the disease, resulting in retinal non-perfusion and breakdown of the blood–retinal barrier with subsequent exudation of fluid, protein and lipid. Such diabetic macular oedema (DME) is the most common cause of blindness among working-age populations in many developed countries.

Blockade of vascular endothelial growth factor-A (VEGF) is remarkably effective in the management of DME. Repeated intravitreal injection of the Food and Drug Administration (FDA)-approved ranibizumab (Lucentis; Genentech, South San Francisco, California, USA)1 2 and aflibercept (Eylea; Regeneron Pharmaceuticals, Tarrytown, New York, USA),3 4 as well as the non-FDA approved bevacizumab (Avastin, Genentech), leads to sustained visual acuity (VA) gains and anatomic improvements.1 3 5 6

Limited prospective data exist concerning the longer term management of patients with DME and DR. In the DRCR.net Protocol I7 and the open-label extension (OLE) following completion of the RIDE (Ranibizumab Injection in Subjects With Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus)/RISE (Ranibizumab Injection in Subjects with Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus) phase III trials,8 initial visual and anatomic gains realised with intensive anti-VEGF therapy were maintained on transition to less frequent ranibizumab dosing.

The ENDURANCE (Long-Term Efficacy and Safety of Intravitreal Aflibercept for the Treatment of DME in Subjects Who Completed the VISTA DME Trial) extension study assessed the ability of an individualised aflibercept retreatment approach to maintain the benefits achieved with aflibercept during the preceding VISTA DME (Study of Intravitreal Aflibercept Injection in Patients With Diabetic Macular Edema) phase III trial.3 Additionally, ENDURANCE assessed the ability of macular laser to decrease treatment burden. Through ENDURANCE week 52, visual and anatomic improvements achieved during VISTA DME were maintained with a mean of 4.5 aflibercept injections, with 30% of patients requiring no retreatment.9 The present manuscript describes outcomes of the second and final year of ENDURANCE.

Methods

The ENDURANCE extension study was a phase IV, open-label study (NCT02299336) aimed at assessing the need for ongoing aflibercept following the 3-year, phase III VISTA DME trial.3 4 All of the patients completing the VISTA DME trial10 at four major clinical sites (n=89) were offered the opportunity to enrol: Retina Consultants of Houston (n=26, Houston, Katy and Woodlands, Texas), Palmetto Retina Center (n=16, West Columbia, South Carolina), Northern California Retina Vitreous Associates (n=9, Mountain View, California) and Retina-Vitreous Associates Medical Group (n=9, Beverly Hills, California). Institutional review board approval was obtained for this Health Insurance Portability and Accountability Act-compliant trial adhering to the tenets of the Declaration of Helsinki. Participants provided written informed consent. Study methods have been described.9 Initially, patients were evaluated every 4 weeks (28±7 days) and treated with aflibercept (2.0 mg) pro re nata in the presence of clinically relevant DME (CR-DME), determined by the investigator as DME limiting optimal visual function in the context of the current VA, spectral-domain optical coherence tomography, dilated ophthalmoscopic examination findings and fluorescein angiography when performed. Patients were eligible for macular laser every 90 days throughout ENDURANCE following eligibility as reported if ≥2 aflibercept injections were given within 90 days.9

Intervals between visits were sequentially lengthened when disease stability was observed without the need for aflibercept retreatments, as reported, to a maximum of 12 weeks through week 52.9 Beginning at week 52, the interval between visits was lengthened beyond 12 weeks to 16 or 20 weeks if no aflibercept retreatment was needed. At any point beyond a 12-week interval, if recurrent CR-DME was identified, the patient received aflibercept and the interval was reduced to a shorter interval at the investigator’s discretion. If the interval needed to be reduced to 4 or 8 weeks, the patient was returned to the core follow-up protocol.9

Of patients who did not complete year 2, corresponding data are included until the date of withdrawal. Time frames for calculating injection totals were baseline to week 52 (inclusive) for year 1, and week 56 to week 104 for year 2, for a maximum of 14 injections in year 1 and 12 in year 2. To be inclusive of patients who did not complete the trial, injection tallies were weighted by the proportion of possible injection visits for which the patient remained in the trial. Conversion from non-proliferative DR (NPDR) to proliferative DR (PDR) was defined as first instance of progression from NPDR to PDR in the clinical record, documented neovascularisation, vitreous haemorrhage or administration of panretinal photocoagulation (PRP). Incidence of first PDR events was evaluated by Kaplan-Meier analysis. Continuous variables were analysed with Student’s t-tests or analysis of variance, and categorical variables were analysed with Χ2 tests or logistic regression. All statistical analyses were performed using R version 3.3.1 (R Project for Statistical Computing, www.r-project.org).

Efficacy analyses were evaluated according to prior treatment group as defined in the VISTA DME phase III trial: 2 mg aflibercept every 4 weeks (Q4), 2 mg aflibercept every 8 weeks after five initial monthly doses (Q8) and macular laser (Laser). The number of patients enrolled in ENDURANCE from the original VISTA DME arms was well balanced.9 For generation of plots for the original VISTA DME study period, outcomes among the Q4 and Q8 arms were pooled, and outcomes for the Laser group include 48% of patients receiving rescue aflibercept dosing beginning at week 24 when prespecified criteria were met.

Results

Sixty patients enrolled in the ENDURANCE extension study between November 2014 and March 2015. Of 54 patients who completed week 52, 46 (85%) patients completed week 104 for an overall completion rate of 77%. Four patients were not followed beyond or withdrew consent at week 52 due to death, scheduling conflicts, difficulty with travel following hospitalisation and personal choice; four additional patients withdrew consent between weeks 52 and 104 due to transportation issues, relocation, personal choice and loss to follow-up.

VA and anatomic outcomes

The mean change in observed ETDRS best-corrected visual acuity (BCVA) remained stable through week 104 of ENDURANCE, fluctuating by no more than three letters at any time point compared with the ENDURANCE baseline (figure 1). The overall mean change in BCVA at week 104 was +0.8 compared with baseline, and there was no significant difference in change in BCVA between patients who received aflibercept injections during ENDURANCE and those who did not (p=0.35). Similarly, there was no difference in BCVA outcomes during ENDURANCE when comparing the original VISTA DME cohorts (p=0.10). Six (10%) and three (5%) patients gained 10 and 15 or more letters through week 104, respectively, while 3 (5%) lost 15 or more letters, 2 due to vitreous haemorrhage related to PDR and 1 due to progression of cataract. Anatomically, as observed through year 1 of ENDURANCE, the mean central retinal thickness (CRT) remained relatively stable through year 2 of ENDURANCE (figure 2).

Figure 1

Graph illustrating mean change in ETDRS best-corrected visual acuity (BCVA) during VISTA DME and ENDURANCE. Aflibercept=patients randomised to intravitreal aflibercept injections during VISTA DME, combining patients in both the monthly aflibercept arm and the every other month aflibercept arm after five monthly loading doses. Laser=patients randomised to the macular laser photocoagulation arm during VISTA DME.

Figure 2

Graph illustrating mean change in central retinal thickness during VISTA DME and ENDURANCE. Aflibercept=patients randomised to intravitreal aflibercept injections during VISTA DME, combining patients in both the monthly aflibercept arm and the every other month aflibercept arm after five monthly loading doses. Laser=patients randomised to the macular laser photocoagulation arm during VISTA DME.

Retreatment frequency

Through week 104 of ENDURANCE, 15 (25%) patients did not demonstrate CR-DME and thus did not require additional aflibercept retreatments to maintain the visual and anatomic gains achieved during the preceding VISTA DME trial. The remaining 45 (75%) patients received at least one injection during ENDURANCE, with 30 (50%) patients receiving 10 or fewer injections, and 3 (5%) patients receiving greater than 20 injections (figure 3).

Figure 3

Distribution of as-needed (PRN) intravitreal aflibercept injections during ENDURANCE. PRN, pro re nata.

Three of 18 (17%) patients who did not experience recurrence of CR-DME in year 1 of ENDURANCE required injections in year 2, receiving 1, 1 and 5 injections during the second year, respectively. Eight of 42 (19%) patients who received aflibercept injections during the first year of ENDURANCE did not require any retreatment in year 2; six (75%) of these patients received three or fewer injections through the entire study period. Overall, the weighted mean number of aflibercept injections through week 104 was 7.7, with weighted means of 4.5 injections in year 1 and 3.4 injections in year 2. Among patients who received at least one injection through week 104, the weighted mean number of injections during ENDURANCE was 9.5.

Among patients who completed at least 12 weeks of ENDURANCE, 44 (77%) met stability criteria at three consecutive visits and were extended beyond a 4-week visit interval at least once through week 104, while 13 (23%) patients never met the criteria for extension of their visit interval. Among patients who completed week 104, 14 (30%) were at an interval between visits of 12 or more weeks; two (14%) of these were at a 16-week interval, and 8 (57%) were at a 20-week interval.

Across 2 years, 27 (45%) patients received a total of 57 macular laser sessions, for a mean of 1.5 laser sessions per patient eligible for macular laser with a mean time to first session of 28 weeks. Fifteen (26%) of these sessions, among 13 patients, occurred in the second year of the trial. Between weeks 52 and 104, two patients met the eligibility criteria for macular laser for the first time at weeks 88 and 92, although laser was not administered in either patient due to the presence of foveal scarring and no treatable microaneurysms by fluorescein angiography. Among those who received macular laser, a mean of 12.6 aflibercept injections were administered through week 104, with an annualised 7.5 and 6.7 mean injections before and after first macular laser application, respectively (p=0.38). The application of laser did not appear to impact VA or anatomic outcomes. The mean changes in VA from baseline to time of first laser application and from first laser application to week 104 were +0.4 and +0.3 ETDRS letters, respectively. The mean changes in CRT from baseline to time of first laser application and from first laser application to week 104 were −9 µm and −7 µm, respectively.

DR outcomes

Gross DR levels through week 104 are presented in table 1. Overall, DR severity appeared to worsen mildly over the 2-year study period, and there appeared to be a possible relationship between DR worsening and fewer aflibercept retreatments. Among patients completing week 104, when data were stratified based on the median number of aflibercept retreatments (7), DR worsening at week 104 was observed more frequently among patients receiving six or fewer compared with patients receiving seven or more (p=0.03). However, logistic regression found no significant relationship between the number of aflibercept retreatments and DR worsening at week 104 (p=0.10).

Table 1

Diabetic retinopathy severity during ENDURANCE

Six patients (10%) experienced conversion from NPDR to PDR at a mean of 492 days (range 161–706), with aflibercept injection frequencies of 0, 1, 3, 3, 8 and 9 through week 104. Of four patients who developed PDR during the second year of ENDURANCE, two developed neovascularisation and two presented with vitreous haemorrhages. Over the course of the complete 104 weeks of ENDURANCE, PDR events were observed in 8 (13%) unique patients (figure 4) at a mean of 387 days (range 141–706) following the prior aflibercept injection, or the beginning of the study if no injection had been administered during ENDURANCE at the time of the PDR event. Following conversion to PDR, three patients received combination therapy with the addition of PRP in the context of ongoing aflibercept injections, while three patients received pharmacological monotherapy.

Figure 4

Kaplan-Meier curve showing cumulative incidence of proliferative diabetic retinopathy (PDR) events during ENDURANCE. 

Safety

No new safety signals were identified in year 2 of ENDURANCE. Ocular adverse events (AEs) and serious adverse events (SAEs) are summarised in table 2. Complications related to DR progression were the most commonly experienced ocular AE, including six vitreous haemorrhages (two graded as severe causing acute visual losses of 50 and 70 letters, and three graded as mild), three instances of neovascularisation in the mid-periphery and one instance of neovascularisation of the disc. In the second year of ENDURANCE, one patient passed away due to myocardial infarction and one experienced a cerebrovascular accident.

Table 2

Adverse events in year 2 of ENDURANCE

Discussion

The complete 2-year ENDURANCE extension study found that the visual and CRT improvements achieved with fixed intravitreal aflibercept dosing during the 3-year VISTA DME phase III trial were maintained, with individualised dosing resulting in a substantially reduced treatment frequency. Across 2 years of management, 25% of patients did not demonstrate recurrence of DME requiring retreatment, and 48% of patients received five or fewer aflibercept retreatments. This is consistent with prior reports noting a clinically meaningful proportion of patients maintaining quiescent disease after stability is achieved.7 8 Following completion of the RIDE/RISE phase III trials, the OLE reported that 24.2% of patients received no additional ranibizumab injections through a mean follow-up of 14.1 months.8

Nevertheless, during ENDURANCE, the overall mean 2-year treatment burden was 7.7 intravitreal aflibercept injections. When data from the OLE8 and ENDURANCE are considered together, both patient populations appeared to require three to four injections annually for control of DME in the fourth to fifth years following initiation of DME management. This indicates that the underlying disease process continues to be active in a substantial proportion of patients. In this context, the application of macular laser to patients receiving at least two aflibercept treatments within ≤24 weeks did not appear to significantly reduce ongoing need for aflibercept retreatments or alter visual and anatomic outcomes.

Many prospective trials have demonstrated the value of pharmacotherapy on modifying DR severity.11 Both anti-VEGF and corticosteroid treatments can significantly slow progression to PDR,12 13 and regular anti-VEGF treatments in particular have demonstrated an ability to improve DR severity levels in a substantial proportion of patients.4 13 14 In comparison, few prospective trials have considered the impact of transition from fixed anti-VEGF dosing to individualised dosing on DR outcomes, and few have evaluated DR outcomes beyond 3 years of anti-VEGF treatment. Two key clinical findings from the DRCR.net Protocol T analysis of DR severity14 align with the current findings. First, there was a strong association between the total number of injections and DR improvement in the Protocol T data set—eyes that received more injections were more likely to demonstrate DR improvements.14 Similarly, in the current ENDURANCE data set, when differentiated by the median number of retreatments through 2 years, receiving fewer injections correlated with greater frequency of DR worsening. Second, in the Protocol T analysis, approximately one-third of eyes that manifested DR improvements at 1 year lost these improvements by the 2-year visit, likely related to the reduced number of retreatments in the second year in all three study arms.14

During the 2-year ENDURANCE extension study, 10% of eyes progressed from NPDR to PDR for the first time, with new PDR events occurring at an average of approximately 1 year after the previous aflibercept injection without development of CR-DME in between. This emphasises the clinical need to consider both a patient’s DME status as well as the DR status when determining management plans and intervals between visits. Ongoing prospective trials may further inform the use of anti-VEGF therapy in the management of DR without DME.15–17

Strengths of the ENDURANCE extension study are its prospective design, well-defined patient cohorts and high protocol compliance. Limitations of the ENDURANCE extension study include the small study population and employment of aflibercept retreatment criteria that allowed physicians to use their clinical judgement in determining need for anti-VEGF treatment instead of a strict protocol.

On a population basis, the long-term management burden through 5 years for patients with DR and DME appears to be substantial. While a clinically relevant minority of patients will not need anti-VEGF dosing for DME, the majority of patients require ongoing clinical evaluation and repeated treatments. New treatment options that address the burden of care for both DME and DR management are needed.

References

Footnotes

  • Contributors Research design: CCW. Data acquisition and/or research execution: CCW, WCO, RNK, DMB, WLC, DSB. Data analysis and/or interpretation: CCW, WCO. Manuscript preparation: CCW, WCO, RNK, DMB, WLC, DSB.

  • Funding Research grant from Regeneron, Tarrytown, NY. The funding organization had no role in the design or conduct of this research.

  • Competing interests All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare financial support for the submitted work from Regeneron, Tarrytown, New York. CCW reports grants and personal fees from Alcon, grants from Allegro, grants and personal fees from Allergan, grants from Apellis, grants from Aura, grants and personal fees from Clearside, grants and personal fees from Genentech, grants and personal fees from Iconic Therapeutics, grants from NEI, grants from NIH, grants from Novartis, grants from Ohr Pharmaceuticals, grants from Ophthotech, grants from pSivida, grants and personal fees from Regeneron, grants from Roche, grants from Santen, grants from SciFluor, grants from Tyrogenex, personal fees from Alimera Sciences, personal fees from Alnylam Pharmaceuticals, personal fees from Bayer, personal fees from DORC, personal fees from ONL Therapeutics, personal fees from ThromboGenics and personal fees from Valeant. RNK reports grants and personal fees from Allergan, personal fees from Genentech, grants and personal fees from Regeneron, grants and personal fees from Santen and grants from Clearside Biomedical. DMB reports grants and personal fees from Regeneron, personal fees from Bayer, personal fees from Adverum, grants and personal fees from Allergan, grants and personal fees from Regenxbio, grants from Clearside Biomedical, grants and personal fees from Ohr, personal fees from Bayer, personal fees from Heidelberg, grants and personal fees from Novartis, personal fees from Optos, personal fees from Zeiss, grants and personal fees from ThromboGenics, grants from Ophthotech and grants from NEI. WLC reports grants and personal fees from Genentech/Roche, grants and personal fees from Ohr Pharmaceuticals, grants from Allergan, grants from Aerpio, and grants, personal fees and non-financial support from Regeneron Pharmaceuticals. DSB reports personal fees from Allergan, personal fees from Alcon, personal fees from Novartis, personal fees from Genentech, personal fees from Roche, personal fees from Bayer, personal fees from Regeneron, personal fees and other from Allegro. No other relationships or activities that could appear to have influenced the submitted work.

  • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

  • Ethics approval Sterling Institutional Review Board, Atlanta, GA.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Collaborators Members of the ENDURANCE Study Group: CCW, WCO, RNK, DMB, WLC, DSB, Alok S. Bansal, Matthew S. Benz, Edwin E. Boldrey, J. Luigi Borrillo, Louis K. Chang, Eric Chen, Thomas G. Chu, Pouya N. Dayani, Daniel Esmaili, Richard H. Fish, Christopher R. Henry, David L. Johnson, Rosa Y. Kim, Ryan T. Le, David Liao, James C. Major Jr, Roger L. Novack, Ronan E. O’Malley, James D. Palmer, John F. Payne, Firas M. Rahhal, Richard H. Roe, Amy C. Schefler, Ankoor R. Shah, Homayoun Tabandeh, Rui Wang, John A. Wells III, Mark R. Wieland, Tien P. Wong.

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