Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

Long-Term Vision Outcomes in Patients With DME and a Limited Early Visual Response to Ranibizumab in RIDE and RISE

Rishi P. Singh, MD; Dante J. Pieramici, MD; Pin-wen Wang, PhD; Shamika Gune, MD

Abstract

BACKGROUND AND OBJECTIVE:

To compare early and long-term visual responses to ranibizumab in patients with diabetic macular edema.

PATIENTS AND METHODS:

Retrospective analysis of RIDE (NCT00473382) and RISE (NCT00473330). Vision outcomes over 36 months were compared between limited early gainers (gained ≤ 5 Early Treatment Diabetic Retinopathy Study [ETDRS] letters), early 1-line gainers (gained 6 to 9 ETDRS letters), and early 2-or-more-line gainers (gained ≥ 10 ETDRS letters) at Month 3.

RESULTS:

Among 235 ranibizumab-treated patients, 42.6%, 20.0%, and 37.4% were limited early gainers, early 1-line gainers, and early 2-or-more-line gainers, respectively. At Month 36, 71.3% of limited early gainers achieved 6 to 9 and 10 or more ETDRS letter gains. Mean ETDRS letter scores at Month 36 were comparable between limited early gainers (67.8), early 1-line gainers (73.4), and early 2-or-more-line gainers (71.6).

CONCLUSION:

Clinically meaningful vision outcomes were achieved with long-term ranibizumab treatment, irrespective of early visual acuity response.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:210–218.]

Abstract

BACKGROUND AND OBJECTIVE:

To compare early and long-term visual responses to ranibizumab in patients with diabetic macular edema.

PATIENTS AND METHODS:

Retrospective analysis of RIDE (NCT00473382) and RISE (NCT00473330). Vision outcomes over 36 months were compared between limited early gainers (gained ≤ 5 Early Treatment Diabetic Retinopathy Study [ETDRS] letters), early 1-line gainers (gained 6 to 9 ETDRS letters), and early 2-or-more-line gainers (gained ≥ 10 ETDRS letters) at Month 3.

RESULTS:

Among 235 ranibizumab-treated patients, 42.6%, 20.0%, and 37.4% were limited early gainers, early 1-line gainers, and early 2-or-more-line gainers, respectively. At Month 36, 71.3% of limited early gainers achieved 6 to 9 and 10 or more ETDRS letter gains. Mean ETDRS letter scores at Month 36 were comparable between limited early gainers (67.8), early 1-line gainers (73.4), and early 2-or-more-line gainers (71.6).

CONCLUSION:

Clinically meaningful vision outcomes were achieved with long-term ranibizumab treatment, irrespective of early visual acuity response.

[Ophthalmic Surg Lasers Imaging Retina. 2020;51:210–218.]

Introduction

Anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for patients with diabetic macular edema (DME), along with medical and lifestyle interventions to improve blood glucose control and other metabolic derangements.1 Clinical trial data show that intravitreal injections of ranibizumab (Lucentis; Genentech, South San Francisco, CA),2,3 aflibercept (Eylea; Regeneron, Tarrytown, NY),4,5 or bevacizumab (Avastin; Genentech, South San Francisco, CA)6 are superior to laser in terms of visual acuity (VA) and optical coherence tomography outcomes for up to 2 years. Improvements observed with anti-VEGF therapy are generally rapid, with clinically meaningful VA gains versus laser often achieved within 3 months.2,5 In the phase 3 RIDE and RISE trials of adults with vision loss due to DME, statistically significant VA and anatomical improvements were observed as early as 7 days after the first ranibizumab injection.7

At present, clinical decisions are often based on anatomical responses to treatment, and retina specialists frequently consider alternative anti-VEGF therapies after 3 to 6 months of limited response.8–10 However, treatment decisions based on short-term and/or anatomical data are not supported by evidence describing long-term functional outcomes.8–10 Previously, a post hoc subgroup analysis of RIDE/RISE revealed that patients who continued monthly ranibizumab treatment despite a limited early anatomical response (≤ 10% reduction in central foveal thickness [CFT] at Month 3) achieved 2-year VA gains and diabetic retinopathy (DR) improvements that were comparable with those attained by patients with a robust anatomical response at Month 3.9 The Early Anti-VEGF Response and Long-term Efficacy (EARLY) analysis of the Diabetic Retinopathy Clinical Research Network Protocol I study, which assessed the efficacy of ranibizumab plus prompt or deferred laser in patients with DME, found that an early anatomical response to ranibizumab (≥ 20% reduction in CFT at Month 3) was weakly associated with best-corrected VA (BCVA) gains over 3 years.10 These findings collectively demonstrate the discordance between early anatomical and late VA outcomes in DME; however, the EARLY analysis also showed that a suboptimal BCVA response to ranibizumab at Month 3 was suggestive of poor long-term vision outcomes.10

In light of this finding, and given key methodological differences between RIDE/RISE and Protocol I,7,10 there is a need to examine whether early BCVA responses to ranibizumab were prognostic of long-term vision gains in RIDE/RISE. Subsequently, this post hoc analysis compared 36-month vision outcomes between patients who initially exhibited a limited early BCVA response to ranibizumab versus those who achieved robust early vision improvements.

Patients and Methods

As previously described,7 RIDE (NCT00473382) and RISE (NCT00473330) were methodologically identical, randomized, double-masked, sham injection-controlled, phase 3 trials of intravitreal ranibizumab for adults with DME. Both trials were approved by appropriate institutional review boards, conducted in accordance with the Declaration of Helsinki, and all patients provided written informed consent to participate.

Analysis Population

Patients included in the present study were randomized to monthly ranibizumab 0.3 mg in RIDE/RISE (the dose approved for DME and DR management in the United States11) and had valid VA data at Month 3 (n = 235). For completeness, analyses of eligible patients in the ranibizumab 0.5 mg treatment arm (n = 239) are presented in an online Supplementary Appendix (Table A and Figures AD available at www.healio.com/OSLIRetina). Vision outcomes over 36 months were compared between patients categorized as limited early gainers (who gained ≤ 5 Early Treatment Diabetic Retinopathy Study [ETDRS] letters from baseline at Month 3), early 1-line gainers (who gained 6 to 9 ETDRS letters from baseline at Month 3), and early 2-or-more-line gainers (who gained ≥ 10 ETDRS letters from baseline at Month 3).

Baseline Characteristics of Patients Treated With Ranibizumab 0.5 mg, Stratified by BCVA Response at Month 3

Table A:

Baseline Characteristics of Patients Treated With Ranibizumab 0.5 mg, Stratified by BCVA Response at Month 3

Change in best-corrected visual acuity (BCVA) response to ranibizumab 0.5 mg over 36 months in (A) limited early gainers, (B) early 1-line gainers, and (C) early ≥ 2-line gainers. Left panels: BCVA gain from baseline over 36 months was compared with BCVA change at Month 3 to determine the proportion of patients in each subgroup with worsening, stable, and improving vision. Right panels: proportion of patients in each subgroup who gained ≤ 5, 6 to 9, and ≥ 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline over 36 months.

Figure A.

Change in best-corrected visual acuity (BCVA) response to ranibizumab 0.5 mg over 36 months in (A) limited early gainers, (B) early 1-line gainers, and (C) early ≥ 2-line gainers. Left panels: BCVA gain from baseline over 36 months was compared with BCVA change at Month 3 to determine the proportion of patients in each subgroup with worsening, stable, and improving vision. Right panels: proportion of patients in each subgroup who gained ≤ 5, 6 to 9, and ≥ 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline over 36 months.

Mean baseline best-corrected visual acuity (BCVA) and mean BCVA gain over 36 months in limited early gainers (left), early 1-line gainers (center), and early ≥ 2-line gainers (right). Mean BCVA at baseline was measured in the overall population for each subgroup; mean BCVA at each time point (Early Treatment Diabetic Retinopathy Study [ETDRS]) letter score and approximate Snellen equivalent) was measured in patients with sufficient follow-up.

Figure B.

Mean baseline best-corrected visual acuity (BCVA) and mean BCVA gain over 36 months in limited early gainers (left), early 1-line gainers (center), and early ≥ 2-line gainers (right). Mean BCVA at baseline was measured in the overall population for each subgroup; mean BCVA at each time point (Early Treatment Diabetic Retinopathy Study [ETDRS]) letter score and approximate Snellen equivalent) was measured in patients with sufficient follow-up.

Proportion of patients who achieved ≥ 20/40 vision or gained ≥ 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline over 36 months in (A) limited early gainers, (B) early 1-line gainers, and (C) early ≥ 2-line gainers. BCVA = best-corrected visual acuity; NA = not applicable.

Figure C.

Proportion of patients who achieved ≥ 20/40 vision or gained ≥ 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline over 36 months in (A) limited early gainers, (B) early 1-line gainers, and (C) early ≥ 2-line gainers. BCVA = best-corrected visual acuity; NA = not applicable.

Mean best-corrected visual acuity (BCVA) change over 36 months in patients treated with ranibizumab (RBZ) 0.5 mg in RIDE/RISE (left panels) and RBZ 0.5 mg in Protocol I (right panels) who (A) gained < 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline at Month 3; (B) gained 5 to 9 ETDRS letters from baseline at Month 3; and (C) gained ≥ 10 ETDRS letters from baseline at Month 3. RIDE/RISE observed data; sample size varied over time. DRCR.net = Diabetic Retinopathy Clinical Research Network.

Figure D.

Mean best-corrected visual acuity (BCVA) change over 36 months in patients treated with ranibizumab (RBZ) 0.5 mg in RIDE/RISE (left panels) and RBZ 0.5 mg in Protocol I (right panels) who (A) gained < 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline at Month 3; (B) gained 5 to 9 ETDRS letters from baseline at Month 3; and (C) gained ≥ 10 ETDRS letters from baseline at Month 3. RIDE/RISE observed data; sample size varied over time. DRCR.net = Diabetic Retinopathy Clinical Research Network.

Outcome Measures

First, categorical BCVA changes from baseline (gained ≤ 5, 6 to 9, and ≥ 10 ETDRS letters) were measured at Months 6, 12, 24, and 36 to determine the proportion of each subgroup with worsening, stable, or improving vision (Table 1), and to summarize the magnitude of BCVA changes over time. Second, mean baseline BCVA and mean BCVA change over 36 months were compared across subgroups. Lastly, the proportion of each subgroup that gained 15 or more ETDRS letters or achieved 20/40 vision or better (ETDRS letter score, 69–73) was summarized over time.

Definition of Patient Subgroups and Directional Change in BCVA Over 36 Months

Table 1:

Definition of Patient Subgroups and Directional Change in BCVA Over 36 Months

Statistical Analysis

Analyses were based on observed data without imputation for missing values. Descriptive summaries of baseline characteristics and study endpoints were stratified by patient subgroup. Analysis of variance was performed on continuous data; chi-square or Fisher's exact tests were used to analyze binary endpoints. Wilcoxon rank-sum tests compared the baseline distribution of DR severity between subgroups.

Results

Analyses included 235 patients randomized to ranibizumab 0.3 mg in RIDE/RISE and categorized as limited early gainers (n = 100; 42.6%), early 1-line gainers (n = 47; 20.0%), and early 2-or-more-line gainers (n = 88; 37.4%) at Month 3 (Table 1). Baseline characteristics were broadly similar across subgroups, with some differences in age, duration of diabetes, BCVA, and DR severity (Table 2). Pairwise comparisons showed that early 2-or-more-line gainers were significantly younger, had a shorter duration of diabetes, and had worse baseline BCVA than limited early gainers, whereas the likelihood of macular nonperfusion at baseline was higher among early 2-or-more-line gainers and early 1-line gainers versus limited early gainers. Baseline DR severity was also greater among early 2-or-more-line gainers on average compared with limited early gainers and early 1-line gainers. Approximately 40% of early 2-or-more-line gainers had proliferative DR (ETDRS Diabetic Retinopathy Severity Scale level ≥ 60) at baseline versus 20% of early 1-line gainers.

Baseline Characteristics of Patients Treated With Ranibizumab 0.3 mg, Stratified by BCVA Response at Month 3

Table 2:

Baseline Characteristics of Patients Treated With Ranibizumab 0.3 mg, Stratified by BCVA Response at Month 3

Effect of Early Treatment Response on Vision Gains Beyond Month 3

To examine the directional change in vision associated with continued ranibizumab therapy, BCVA changes over 36 months were assessed in each subgroup (Figure 1). Among limited early gainers, 38.0% had improved vision at Month 6, with 16.3% and 21.7% gaining 6 to 9 and 10 or more ETDRS letters, respectively. By Month 36, 71.3% of limited early gainers had achieved 6 to 9 and 10 or more ETDRS letter gains (23.8% and 47.5%, respectively). In early 1-line gainers, 39.5% achieved improved vision gains of 10 or more ETDRS letters at Month 6, increasing to 70.7% at Month 24. By Month 36, more than 80% of early 1-line gainers had either maintained a 6 to 9 ETDRS letter gain or achieved further vision improvement. Similarly, the majority of early 2-or-more-line gainers maintained vision gains of 10 or more ETDRS letters over 36 months. Less than 10% of these patients had reduced vision gains of 6 to 9 and 5 or fewer ETDRS letters at Month 36 (2.7% and 5.4%, respectively).

Change in best-corrected visual acuity (BCVA) response to ranibizumab 0.3 mg over 36 months in (A) limited early gainers, (B) early 1-line gainers, and (C) early ≥ 2-line gainers. Left panels: BCVA gain from baseline over 36 months was compared with BCVA change at Month 3 to determine the proportion of patients in each subgroup with worsening, stable, and improving vision. Right panels: proportion of patients in each subgroup who gained ≤ 5, 6 to 9, and ≥ 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline over 36 months.

Figure 1.

Change in best-corrected visual acuity (BCVA) response to ranibizumab 0.3 mg over 36 months in (A) limited early gainers, (B) early 1-line gainers, and (C) early ≥ 2-line gainers. Left panels: BCVA gain from baseline over 36 months was compared with BCVA change at Month 3 to determine the proportion of patients in each subgroup with worsening, stable, and improving vision. Right panels: proportion of patients in each subgroup who gained ≤ 5, 6 to 9, and ≥ 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline over 36 months.

Given that baseline vision differed between limited early gainers, early 1-line gainers, and early 2-or-more-line gainers, we examined the association between mean BCVA improvement at Months 12, 24, and 36, and mean baseline BCVA in each subgroup (Figure 2). Overall, ranibizumab therapy was associated with mean BCVA gains that increased in magnitude over 36 months. Of the three subgroups, mean BCVA gains at each time point were smallest among limited early gainers and largest among early 2-or-more-line gainers, the subgroup with the lowest baseline BCVA. Despite differences in vision gains over time, mean ETDRS letter scores achieved at Month 36 were comparable across subgroups, owing to differences in mean baseline BCVA. At Month 36, mean BCVA exceeded 67 ETDRS letters (approximate Snellen equivalent, 20/50) in all three subgroups, and was not significantly different between limited early gainers, early 1-line gainers, and early 2-or-more-line gainers (67.8 [∼20/50], 73.4 [∼20/40], and 71.6 [∼20/40], respectively; P = .09).

Mean baseline best-corrected visual acuity (BCVA) and mean BCVA gain over 36 months in limited early gainers (left), early 1-line gainers (center), and early ≥ 2-line gainers (right). Mean BCVA at baseline was measured in the overall population for each subgroup; mean BCVA at each time point (Early Treatment Diabetic Retinopathy Study [ETDRS]) letter score and approximate Snellen equivalent) were measured in patients with sufficient follow-up.

Figure 2.

Mean baseline best-corrected visual acuity (BCVA) and mean BCVA gain over 36 months in limited early gainers (left), early 1-line gainers (center), and early ≥ 2-line gainers (right). Mean BCVA at baseline was measured in the overall population for each subgroup; mean BCVA at each time point (Early Treatment Diabetic Retinopathy Study [ETDRS]) letter score and approximate Snellen equivalent) were measured in patients with sufficient follow-up.

Figure 3 shows the proportion of each subgroup who achieved 20/40 or better vision or gained 15 or more ETDRS letters from baseline over 36 months. Early 2-or-more-line gainers had the lowest proportion of patients with 20/40 or better vision at baseline (6.8%) but had the highest proportion of patients who gained 15 or more ETDRS letters (78.4%) and achieved 20/40 or better vision (71.6%) at Month 36. Approximately 20% of limited early gainers and early 1-line gainers had 20/40 or better vision at baseline; with continued ranibizumab therapy, 60.0% to 70.3% of these patients achieved 20/40 or better vision at Month 36.

Proportion of patients who achieved ≥ 20/40 vision or gained ≥ 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline over 36 months in (A) limited early gainers, (B) early 1-line gainers, and (C) early ≥ 2-line gainers. BCVA = best-corrected visual acuity; NA = not applicable

Figure 3.

Proportion of patients who achieved ≥ 20/40 vision or gained ≥ 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline over 36 months in (A) limited early gainers, (B) early 1-line gainers, and (C) early ≥ 2-line gainers. BCVA = best-corrected visual acuity; NA = not applicable

Discussion

Given the expectation of prompt benefits with anti-VEGF therapy for DME, there is a need to evaluate appropriate treatment response times and to define parameters indicative of treatment failure. Our post hoc analyses explored the relationship between early and long-term BCVA responses to ranibizumab observed in RIDE/RISE and provide valuable insights for future patient management.

Of the 235 ranibizumab-treated patients included in our study, 43% gained 5 or fewer ETDRS letters at Month 3 and were categorized as limited early gainers. Despite initially exhibiting little-to-no BCVA improvement, greater than 70% of this subgroup achieved vision gains at Months 24 and 36 that were improved from those at Month 3. Moreover, continued treatment among limited early gainers resulted in a mean BCVA at Month 36 that was comparable with early 1- and 2-or-more-line gainers. Although BCVA improvements at Month 36 were smaller among limited early gainers (and early 1-line gainers) versus early 2-or-more-line gainers, this observation may be suggestive of a “ceiling effect”12 in limited early gainers, given their better vision and lower incidence of macular nonperfusion at baseline. This was similarly observed in prespecified subgroup analyses of RIDE/RISE, where vision outcomes were improved among patients with lower baseline BCVA (and greater capacity to gain letters over the course of treatment).7 However, consistent with our finding that mean BCVA at Month 36 was comparable between subgroups, sole focus on change from baseline vision outcomes without considering starting VA can lead to a misinterpretation of treatment response. Considering the potential for ceiling or floor effects in categorical analyses, comparisons of VA change as a continuous random variable are deemed the most clinically relevant measure of vision outcomes in studies of retinal diseases.12

When we redefined our subgroups to align with BCVA response categories used in the EARLY analysis of Protocol I,10 long-term vision gains were observed in patients across all early BCVA responses to ranibizumab (Table 3). On average, patients who lost ETDRS letters from baseline at Month 3 went on to gain 7.3 ETDRS letters at Month 36 compared with 9.4 ETDRS letters in patients who initially gained 0 to 4 ETDRS letters, and 14.3 ETDRS letters in those who gained 5 to 9 ETDRS letters at Month 3. By definition, early 2-or-more-line gainers were unable to move to a higher BCVA response category; nevertheless, mean BCVA gains improved from 16.5 ETDRS letters at Month 3 to 19.5 ETDRS letters at Month 36. These findings are consistent with our primary analyses and demonstrate that in patients with a poor early VA response to ranibizumab, further vision gains are achievable with continued therapy.

Early Versus Long-Term Vision Gains Among Patients Treated With Ranibizumab 0.3 mgin RIDE/RISE

Table 3:

Early Versus Long-Term Vision Gains Among Patients Treated With Ranibizumab 0.3 mgin RIDE/RISE

Long-term vision gains observed in this study were larger than those reported in the EARLY analysis of Protocol I (Figure 4).10 In RIDE/RISE and Protocol I, a similar proportion of eyes gained less than 5, 5 to 9, and 10 or more ETDRS letters from baseline at Month 3; however, mean BCVA gains from Months 3 to 36 were smaller among Protocol I subgroups. Key methodological differences likely explain the observed disparity in long-term VA responses to ranibizumab.7,10,13 In RIDE/RISE, patients randomized to ranibizumab were monitored monthly, received monthly injections through Month 36, and received macular laser as rescue therapy according to prespecified criteria.7,14 In Protocol I, ranibizumab was administered as needed after Month 4, whereby eyes that did not achieve “treatment success” based on predefined visual and anatomical improvements were recommended for re-treatment.13 As a result, the median number of ranibizumab injections over 36 months ranged between 12 and 15 in patients randomized to prompt or deferred laser in Protocol I,15 compared with 34 to 35 across ranibizumab treatment arms in RIDE/RISE.14 In addition, patients were monitored every 4 to 16 weeks from Month 24 in Protocol I, and focal/grid laser treatment was given on a prompt or deferred basis.13 In patients who did not receive prompt focal/grid laser, rates of laser treatment were generally comparable between studies. In RIDE/RISE, 20% to 39% of ranibizumab-treated patients received macular laser through Month 24,7 whereas 42% of patients in the ranibizumab plus deferred laser group of Protocol I received at least one session of focal/grid laser through the 2-year visit.16 Nevertheless, frequent injections and regular monitoring likely accounted for the steady BCVA improvement over 36 months in RIDE/RISE, greater than that reported in Protocol I.10 With as-needed ranibizumab treatment and less-stringent patient monitoring, only 20% to 30% of eyes with limited early vision gains achieved a mean BCVA gain of 10 or more ETDRS letters at Month 36 of Protocol I.10

Mean best-corrected visual acuity (BCVA) change over 36 months in patients treated with ranibizumab (RBZ) 0.3 mg in RIDE/RISE (left panels) and RBZ 0.5 mg in Protocol I (right panels) who (A) gained < 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline at Month 3; (B) gained 5 to 9 ETDRS letters from baseline at Month 3; and (C) gained ≥ 10 ETDRS letters from baseline at Month 3. RIDE/RISE observed data; sample size varied over time. DRCR.net = Diabetic Retinopathy Clinical Research Network; EARLY = Early Anti-VEGF Response and Long-term Efficacy

Figure 4.

Mean best-corrected visual acuity (BCVA) change over 36 months in patients treated with ranibizumab (RBZ) 0.3 mg in RIDE/RISE (left panels) and RBZ 0.5 mg in Protocol I (right panels) who (A) gained < 5 Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline at Month 3; (B) gained 5 to 9 ETDRS letters from baseline at Month 3; and (C) gained ≥ 10 ETDRS letters from baseline at Month 3. RIDE/RISE observed data; sample size varied over time. DRCR.net = Diabetic Retinopathy Clinical Research Network; EARLY = Early Anti-VEGF Response and Long-term Efficacy

It is unclear why some patients are slow to achieve VA improvement with ranibizumab. Limited early response due to a delayed anatomical response is unlikely, given the finding that only 10% of patients in the ranibizumab 0.3 mg arm of RIDE/RISE exhibited a 10% or less reduction in CFT at Month 3.9 Moreover, patients with a delayed anatomical response not only had BCVA similar to early anatomical responders at baseline, but also achieved comparable BCVA improvements at Month 3.9 Nevertheless, it is possible that BCVA responses to ranibizumab lag behind anatomical improvement, and that limited early gainers may benefit from an intensive anti-VEGF treatment regimen, such as that followed in RIDE/RISE. Heterogeneous patient responses to anti-VEGF therapy have also been reported,5,6,14,17 which is not surprising given the complex nature of DME. In addition to a range of genotypic and phenotypic factors that could affect anti-VEGF treatment response,10 the extent of VEGF elevation in the vitreous of patients with and without DME is also highly variable.18

There are inherent limitations associated with this retrospective study. In particular, our analyses were not prespecified and may be underpowered for intergroup comparisons. Although our data suggest that, in patients with DME and a limited early VA response to ranibizumab, further vision gains are achievable with continued therapy, they should not be taken to conclude that this strategy is superior to treatment with alternative or additional agents. Rather, our findings are hypothesis generating and highlight the need for prospective studies to characterize the interrelationships between anatomical, physiological, and functional responses to treatment, as well as to optimize future DME management.

In conclusion, this post hoc analysis of RIDE/RISE found that clinically meaningful vision improvements were achieved by patients randomized to monthly intravitreal ranibizumab over 36 months, irrespective of their response to treatment after 3 months. We showed that the majority of patients categorized as limited early gainers at Month 3 went on to achieve visual improvements over 36 months that were comparable with patients who demonstrated a robust early treatment response. These data support the notion of continued anti-VEGF therapy in patients with DME, because further vision gains were achievable in most patients, including those who initially exhibited a modest response to ranibizumab.

Data Sharing Statement

Qualified researchers may request access to individual patient level data through the clinical study data request platform ( www.clinicalstudydatarequest.com). Further details on Roche's criteria for eligible studies are available at https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Roche.aspx. Further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents are available at https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm.

References

  1. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern guidelines. Diabetic retinopathy. AAO website. https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp-updated-2017. Accessed May 14, 2019.
  2. Nguyen QD, Shah SM, Heier JS, et al. READ-2 Study Group. Primary end point (six months) results of the Ranibizumab for Edema of the mAcula in Diabetes (READ-2) study. Ophthalmology. 2009;116(11):2175–81.e1. doi:10.1016/j.ophtha.2009.04.023 [CrossRef] PMID:19700194
  3. Nguyen QD, Shah SM, Khwaja AA, et al. READ-2 Study Group. Two-year outcomes of the ranibizumab for edema of the macula in diabetes (READ-2) study. Ophthalmology. 2010;117(11):2146–2151. doi:10.1016/j.ophtha.2010.08.016 [CrossRef] PMID:20855114
  4. Do DV, Nguyen QD, Boyer D, et al. da Vinci Study Group. One-year outcomes of the da Vinci Study of VEGF Trap-Eye in eyes with diabetic macular edema. Ophthalmology. 2012;119(8):1658–1665. doi:10.1016/j.ophtha.2012.02.010 [CrossRef] PMID:22537617
  5. Brown DM, Schmidt-Erfurth U, Do DV, et al. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies. Ophthalmology. 2015;122(10):2044–2052. doi:10.1016/j.ophtha.2015.06.017 [CrossRef] PMID:26198808
  6. Rajendram R, Fraser-Bell S, Kaines A, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: report 3. Arch Ophthalmol. 2012;130(8):972–979. doi:10.1001/archophthalmol.2012.393 [CrossRef] PMID:22491395
  7. Nguyen QD, Brown DM, Marcus DMRISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012;119(4):789–801. doi:10.1016/j.ophtha.2011.12.039 [CrossRef] PMID:22330964
  8. Rezaei KA, Stone TW. 2015Global Trends in Retina Survey. https://www.asrs.org/content/documents/2015_global_trends_in_retina_survey_-_for_website.pdf. Accessed May 14, 2019.
  9. Pieramici DJ, Wang PW, Ding B, Gune S. Visual and anatomic outcomes in patients with diabetic macular edema with limited initial anatomic response to ranibizumab in RIDE and RISE. Ophthalmology. 2016;123(6):1345–1350. doi:10.1016/j.ophtha.2016.02.007 [CrossRef] PMID:26992841
  10. Gonzalez VH, Campbell J, Holekamp NM, et al. Early and long-term responses to anti–vascular endothelial growth factor therapy in diabetic macular edema: analysis of Protocol I data. Am J Ophthalmol. 2016;172:72–79. doi:10.1016/j.ajo.2016.09.012 [CrossRef] PMID:27644589
  11. Lucentis. [package insert]. South San Francisco, CA: Genentech, Inc; 2018.
  12. Beck RW, Maguire MG, Bressler NM, Glassman AR, Lindblad AS, Ferris FL. Visual acuity as an outcome measure in clinical trials of retinal diseases. Ophthalmology. 2007;114(10):1804–1809. doi:10.1016/j.ophtha.2007.06.047 [CrossRef] PMID:17908590
  13. Elman MJ, Aiello LP, Beck RW, et al. Diabetic Retinopathy Clinical Research Network. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117(6):1064–1077.e35. doi:10.1016/j.ophtha.2010.02.031 [CrossRef] PMID:20427088
  14. Brown DM, Nguyen QD, Marcus DM, et al. RIDE and RISE Research Group. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013;120(10):2013–2022. doi:10.1016/j.ophtha.2013.02.034 [CrossRef] PMID:23706949
  15. Elman MJ, Qin H, Aiello LP, et al. Diabetic Retinopathy Clinical Research Network. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology. 2012;119(11):2312–2318. doi:10.1016/j.ophtha.2012.08.022 [CrossRef] PMID:22999634
  16. Elman MJ, Bressler NM, Qin H, et al. Diabetic Retinopathy Clinical Research Network. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118(4):609–614. doi:10.1016/j.ophtha.2010.12.033 [CrossRef] PMID:21459214
  17. Wells JA, Glassman AR, Ayala AR, et al. Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193–1203. doi:10.1056/NEJMoa1414264 [CrossRef] PMID:25692915
  18. Funatsu H, Noma H, Mimura T, Eguchi S, Hori S. Association of vitreous inflammatory factors with diabetic macular edema. Ophthalmology. 2009;116(1):73–79. doi:10.1016/j.ophtha.2008.09.037 [CrossRef] PMID:19118698

Definition of Patient Subgroups and Directional Change in BCVA Over 36 Months

Patient Subgroup*BCVA Gain From Baseline at Month 3, ETDRS LettersBCVA Gain From Baseline at Month 36, ETDRSLetters
≤ 56–9≥10
Limited early gainers≤ 5StableImprovedImproved
Early 1-line gainers6–9WorsenedStableImproved
Early ≥ 2-line gainers≥ 10WorsenedWorsenedStable

Baseline Characteristics of Patients Treated With Ranibizumab 0.3 mg, Stratified by BCVA Response at Month 3

Baseline CharacteristicRanibizumab 0.3 mg (n = 235)

Limited Early Gainers* (n = 100)Early 1-Line Gainers (n = 47)Early ≥ 2-Line Gainers (n = 88)
Mean (SD) age, years64.6 (8.8)60.6 (12.9)60.3 (9.4)§

Female, n (%)49 (49.0)16 (34.0)31 (35.2)

Race, n (%)
  White76 (76.0)39 (83.0)71 (80.7)
  Black/African American18 (18.0)1 (2.1)9 (10.2)
  Asian2 (2.0)4 (8.5)6 (6.8)
  Native Hawaiian/other Pacific Islander1 (1.0)1 (2.1)1 (1.1)
  American Indian/Alaskan Native0 (0.0)0 (0.0)0 (0.0)
  Not available3 (3.0)2 (4.3)1 (1.1)

Mean (SD) diabetes duration, years17.3 (10.2)16.6 (10.8)13.8 (8.9)§

Mean (SD) HbA1c, %7.6 (1.3)7.9 (1.5)7.6 (1.4)

Mean (SD) BCVA, ETDRS letter score57.9 (12.3)58.9 (10.5)52.3 (11.7)§,‖

Approximate Snellen equivalent20/8020/8020/100

Mean (SD) CFT, μm462.3 (157.8)467.4 (180.8)499.4 (155.6)

Macular nonperfusion, n (%)11 (12.5)13 (35.1)§32 (41.6)§

DR severity
  ETDRS-DRSS level, n (%)
    1 = DRSS level 10, 12 (DR absent)0 (0.0)1 (2.2)0 (0.0)
    2 = DRSS level 14A-14C, 14Z, 15, 20 (DR questionable, microaneurysms only)3 (3.3)0 (0.0)0 (0.0)
    3 = DRSS level 35A-35F (mild NPDR)22 (24.2)8 (17.8)7 (8.3)
    4 = DRSS level 43A-43B (moderate NPDR)12 (13.2)6 (13.3)8 (9.5)
    5 = DRSS level 47A-47D (moderately severe NPDR)18 (19.8)19 (42.2)29 (34.5)
    6 = DRSS level 53A-53E (severe NPDR)5 (5.5)2 (4.4)7 (8.3)
    7 = DRSS level 60, 61A, 61B (mild PDR)27 (29.7)8 (17.8)28 (33.3)
    8 = DRSS level 65A-65C (moderate PDR)4 (4.4)1 (2.2)2 (2.4)
    9 = DRSS level 71A-71D (high-risk PDR)0 (0.0)0 (0.0)3 (3.6)
    10 = DRSS level 75 (high-risk PDR)0 (0.0)0 (0.0)0 (0.0)

Median (IQR)5.0 (3–7)5.0 (4–5)5.0 (5–7)§,‖

Early Versus Long-Term Vision Gains Among Patients Treated With Ranibizumab 0.3 mgin RIDE/RISE

BCVA Change From Baseline at Month 3n (%)Mean BCVA Change From Baseline, ETDRS Letters
Month 3Month 36
Lost ETDRS letters33 (14.0)−6.87.3
Gained 0-4 ETDRS letters54 (23.0)2.29.4
Gained 5–9 ETDRS letters60 (25.5)7.014.3
Gained ≥ 10 ETDRS letters88 (37.4)16.519.5

Baseline Characteristics of Patients Treated With Ranibizumab 0.5 mg, Stratified by BCVA Response at Month 3

Baseline Characteristic*Ranibizumab 0.5 mg (n = 239)

Limited Early Gainers (n = 88)Early 1-Line Gainers (n = 46)Early ≥ 2-Line Gainers§ (n = 105)

Mean (SD) age, years62.3 (8.9)64.3 (9.4)60.7 (10.7)

Female, n (%)35 (39.8)20 (43.5)45 (42.9)

Race, n (%)
  White67 (76.1)40 (87.0)86 (81.9)
  Black/African American12 (13.6)3 (6.5)10 (9.5)
  Asian4 (4.5)2 (4.4)5 (4.8)
  Native Hawaiian/other Pacific Islander0 (0.0)0 (0.0)1 (1.0)
  American Indian/Alaskan Native2 (2.3)0 (0.0)0 (0.0)
  Not available3 (3.4)1 (2.2)3 (2.9)

Mean (SD) diabetes duration, years15.4 (9.4)16.6 (8.7)15.8 (9.9)

Mean (SD) HbA1c, %7.8 (1.6)7.8 (1.3)7.4 (1.3)

Mean (SD) BCVA, ETDRS letter score58.8 (12.0)56.8 (10.8)55.1 (11.5)

Approximate Snellen equivalent20/8020/8020/80

Mean (SD) CFT, μm469.9 (176.8)453.2 (135.3)479.8 (155.8)

Macular nonperfusion, n (%)17 (21.8)13 (31.0)26 (27.7)

DR severity
  ETDRS-DRSS level, n (%)
    1 = DRSS level 10, 12 (DR absent)0 (0.0)0 (0.0)1 (1.0)
    2 = DRSS level 14A-14C, 14Z, 15, 20 (DR questionable, microaneurysms only)1 (1.2)0 (0.0)1 (1.0)
    3 = DRSS level 35A-35F (mild NPDR)17 (21.0)8 (18.6)14 (14.1)
    4 = DRSS level 43A-43B (moderate NPDR)15 (18.5)5 (11.6)12 (12.1)
    5 = DRSS level 47A-47D (moderately severe NPDR)17 (21.0)19 (44.2)28 (28.3)
    6 = DRSS level 53A-53E (severe NPDR)4 (4.9)1 (2.3)3 (3.0)
    7 = DRSS level 60, 61A, 61B (mild PDR)24 (29.6)9 (20.9)34 (34.3)
    8 = DRSS level 65A-65C (moderate PDR)3 (3.7)1 (2.3)4 (4.0)
    9 = DRSS level 71A-71D (high-risk PDR)0 (0.0)0 (0.0)1 (1.0)
    10 = DRSS level 75 (high-risk PDR)0 (0.0)0 (0.0)1 (1.0)

Median (IQR)5.0 (4–7)5.0 (4–6)5.0 (4–7)
Authors

From the Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland, Ohio (RPS); California Retina Consultants, Santa Barbara, California (DJP); and Genentech, Inc., South San Francisco, California (PW, SG).

Presented in part at the 49th Annual Scientific Meeting of the Retina Society, September 14-17, 2016, San Diego, CA; and the 20th Annual Club VIT Annual Meeting, June 28–July 1, 2017, Mykonos, Greece.

Supported by Genentech, Inc., a member of the Roche Group. The sponsor participated in study design; collection, analysis, and interpretation of data; writing the report; and the decision to submit the report for publication. Third-party writing assistance, provided by Karina D. Hamilton-Peel, PhD, CMPP, and Betsy C. Taylor, PhD, CMPP, of Envision Pharma Group, was funded by Genentech, Inc.

Dr. Singh is a consultant for Alcon, Genentech, Optos, Regeneron, and Zeiss and receives research payment from Alcon, Apellis, Genentech, Regeneron, and Roche. Dr. Pieramici is a consultant for Alimera, Allergan, Genentech, Santen, and ThromboGenics. Dr. Wang was an employee of Genentech during the course of this study (current employee of Philips Healthcare, Seattle, WA). Dr. Gune is an employee of Genentech.

Dr. Singh did not participate in the editorial review of this manuscript.

Address correspondence to Rishi P. Singh, MD, Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, 9500 Euclid Avenue, i-32, Cleveland, OH 44195; email: drrishisingh@gmail.com.

Received: October 15, 2019
Accepted: January 16, 2020

10.3928/23258160-20200326-02

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