Bimonthly, treat‐and‐extend and as‐needed ranibizumab in naïve neovascular age‐related macular degeneration patients: 12‐month outcomes of a randomized study

Abstract

To assess the noninferiority of the treat-and-extend (T&E) and fixed bimonthly regimens of 0.5 mg intravitreal ranibizumab as compared with the pro re nata (PRN) in na€ ıve patients with neovascular age-related macular degeneration (nAMD). Methods: Phase IV, randomized, 12-month, multicentre trial. Patients aged ≥50 years with nAMD and visual impairment [best-corrected visual acuity (BCVA) between 23 and 78 Early Treatment Diabetic Retinopathy Study (ETDRS) letters] were eligible. Patients (one eye per patient) were randomized to bimonthly, n = 103, T&E, n = 99 or PRN, n = 104. Noninferiority was established at five letters ETDRS. Results: The mean (95% CI) difference in BCVA at 12 months was 7.2 (4.2-10.2), 6.4 (2.9-9.8), and 8.0 (51.1-11.0) in the bimonthly, T&E and PRN, respectively. The bimonthly or T&E regimens were not inferior to the PRN scheme. All regimens were associated with a significant reduction of central subfield thickness and volume. The mean (95% CI) number of injections in the bimonthly regimen (7.6, 7.5-7.7) was similar as compared with the PRN regimen (7.4, 6.7-8.0) (p = 0.159) but lower than in the T&E regimen (9.3, 8.9-9.7) (p < 0.001). Conclusion: At 12 months, bimonthly and T&E ranibizumab were noninferior to PRN in na€ ıve nAMD. Key words: best-corrected visual acuity-fixed bimonthly-intravitreal anti-VEGF-neovascular age-related macular degeneration-pro re nata-ranibizumab-treat-and-extend † The In-Eye Study Group members are listed in Appendix 1.

Treat-and-Extend Regimens for the Management of Neovascular Age-related Macular Degeneration and Polypoidal Choroidal Vasculopathy: Consensus and Recommendations From the Asia-Pacific Vitreo-retina Society

“…The In-Eye trial reported a greater mean number of injections and clinic visits with ranibizumab T&E compared with bimonthly dosing over 12 months (injections: 9.3 vs 7.6; visits: 10.4 vs 8.6, respectively; P < 0.001). 33 In the ARIES trial, the early-start T&E arm received approximately one fewer injection over 12 months than the late-start T&E arm. 31 This difference was also reflected over 2 years of the ARIES study, with patients in the late-start T&E arm switching to a T&E regimen in the second year.…”

“…In the In-Eye trial, a mean of 9.3 vs 7.4 injections were administered in the ranibizumab T&E and PRN arms, respectively ( P < 0.001), with a mean of 10.4 vs 13.6 clinic visits over 12 months ( P < 0.001). 33 The number of injections with T&E regimens may decrease in subsequent years; however, a head-to-head RCT comparing T&E with PRN strategies beyond 1 year is not yet available. Seven observational studies comparing T&E with PRN regimens reported more injections over the study period with T&E than with PRN 24 , 36 , 39 – 43 ; however, of these studies, the 3 that reported number of clinic visits indicated more visits with PRN than with T&E regimens.…”

“…Fourteen of 22 studies assessing a T&E regimen (excluding meta-analyses) employed a traditional T&E regimen requiring complete resolution of both intraretinal fluid (IRF) and subretinal fluid (SRF) on optical coherence tomography (OCT) as a definition for “inactive disease” to allow extension of the treatment interval. These studies were the CANTREAT, 26 , 30 In-Eye, 33 LUCAS, 44 , 49 RIVAL, 45 , 50 TREND 27 trials, and many observational studies. 24 , 32 , 37 , 39 , 42 , 43 , 46 , 51 However, FLUID, 23 ALTAIR, 20 and ARIES 18 , 31 and 2 observational studies, 41 , 47 have indicated the potential for vision gains with a T&E regimen without the need to aim for complete fluid resolution.…”

“… 63 , 64 , 66 – 70 Given the reported differences in durability (ie, the potential for achieving extended treatment intervals) of each anti-VEGF agent with a T&E regimen in our investigation, with ranibizumab the treatment interval may be extended stepwise by no more than 2 weeks at a time (until signs of disease activity or visual impairment recur) up to a maximum of 12 weeks. To our knowledge, extension of the treatment interval in 4-week increments between visits and treatment intervals of >12 weeks have not been assessed in clinical trials of ranibizumab T&E. 26 , 27 , 30 , 33 , 44 , 49 Based on evidence from the ALTAIR and ARIES trials, the treatment interval with aflibercept T&E may be gradually extended in 2- or 4-week increments up to a maximum of 16 weeks. 18 , 20 …”

“…Although T&E regimens typically require more injections than PRN dosing over the first 12 months, fewer clinic visits are required with T&E in the following years. 24 , 33 , 40 , 42 Moreover, the ALTAIR 20 and ARIES 18 trials and several observational studies have indicated that the frequency of aflibercept injections with T&E regimens can notably decrease in subsequent years of treatment while maintaining vision gains achieved in the first year, further highlighting the benefits of T&E for reducing treatment burden on patients and health care systems. 18 , 20 , 76 – 78 Therefore, the APVRS expert panel recommends the use of T&E regimens for the management of patients with nAMD and PCV in the Asia-Pacific region, with advantages of reducing the burden of frequent clinic visits and providing certainty of scheduled treatment visits while still providing meaningful visual outcomes for patients.…”