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Clinical science
Neovascular age-related macular degeneration management in the third year: final results from the TREX-AMD randomised trial
  1. Charles C Wykoff1,2,
  2. William C Ou1,
  3. Daniel E Croft1,
  4. John F Payne3,
  5. David M Brown1,2,
  6. W Lloyd Clark3,
  7. Nizar Saleh Abdelfattah4,5,
  8. SriniVas R Sadda4,5
  9. for the TREX-AMD 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 Palmetto Retina Center, West Columbia, South Carolina, USA
  4. 4 Doheny Image Reading Center, Doheny Eye Institute, Los Angeles, California, USA
  5. 5 Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
  1. Correspondence to 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 Prospectively evaluate outcomes in the third year of neovascular age-related macular degeneration (AMD) management using ranibizumab with continued treat and extend (TREX) dosing compared with monthly visits with retreatment upon evidence of exudative disease activity (PRN, pro re nata).

Methods Subjects with treatment-naïve neovascular AMD were randomised 1:2 to Monthly or TREX and managed through 2 years. In the third year, subjects randomised to Monthly were managed PRN while subjects randomised to TREX were continued on TREX dosing or transitioned to PRN after achieving an interval of 12 weeks between visits.

Results Sixty subjects enrolled and 46 (77%) completed month 36 (M36). Transition from Monthly to PRN was associated with a decline in best corrected visual acuity (BCVA) (+10.5 letters (month 24) to +5.4 (M36, p=0.09)); three (15%) subjects required no dosing during year 3, and 47% (114/243) of possible PRN injections were delivered, yielding a mean of 6.1 injections during year 3. Among the 9 (23%) TREX subjects transitioned to PRN, the need for ongoing anti-vascular endothelial growth factor retreatments was small, with 4 (4%) intravitreal injections being delivered among 106 PRN visits; this subgroup displayed an inferior BCVA trajectory compared with the remainder of subjects. Outcomes among subjects continued on TREX were more favourable, with a mean gain of +5.0 letters at M36.

Conclusions Upon transition to PRN, subjects randomised to monthly dosing experienced a decline in BCVA. Among subjects initially randomised to TREX who transitioned to PRN after achieving a 12-week interval between visits, the overall need for additional treatment was low.

Trial registration number NCT01748292, Results.

  • clinical trial
  • retina

https://doi.org/10.1136/bjophthalmol-2017-310822

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    Introduction

    Neovascular age-related macular degeneration (AMD), a progressive disease with a well-characterised poor natural history, remains a leading cause of visual impairment. Intravitreally administered pharmaceutical agents that inhibit the activity of vascular endothelial growth factor-A (VEGF) are the mainstay of management. With appropriate treatment, both anatomic disease stability and visual improvement can be achieved in a large proportion of subjects.1–3 In phase III, prospective, randomised trials employing current generation anti-VEGF monotherapies, fixed monthly dosing optimises visual and anatomic outcomes on a population basis.3–7 Despite the potential value, indefinite fixed monthly dosing poses a substantial burden for subjects and healthcare systems across the globe. Therefore, few physicians report practising such strict monthly dosing.8

    The large majority of retina specialists in the USA use a treat and extend (TREX) approach with the hope of achieving the visual benefit of monthly dosing while minimising treatment burden.8 9 TREX dosing has been validated by both retrospective and prospective analyses.10–16 When pursuing TREX, a substantial proportion of subjects ultimately achieve long intervals between injections.14–16 It remains unclear if these subjects require ongoing dosing or if they could maintain clinical stability without ongoing retreatments.

    Another concern in the long-term management of neovascular AMD is episodic recurrence of exudative disease activity, which appears to limit ultimate visual acuity (VA) gains. Chronic underdosing of active neovascular AMD significantly restricts long-term visual benefits on a population basis.17 18 Furthermore, once stability is achieved, mandating substantial VA loss or dramatic increases in macular oedema before allowing anti-VEGF retreatment also significantly curtails ultimate VA.19 20 Moreover, even subtle episodes of recurrence appear to impact ultimate visual potential. In the 2-year Comparison of AMD Treatment Trial (CATT), eyes transitioned from monthly dosing to monthly visits with retreatment only upon evidence of exudative disease activity (PRN, pro re nata) after 1 year demonstrated a loss of subsequent VA on average to the level observed among subjects initially randomised to PRN management.5 It remains unknown if a longer duration of monthly dosing may have mitigated this decline.

    The TREX-AMD (TReat and EXtend Protocol in Patients with Wet Age-related Macular Degeneration) study was a prospective, randomised trial directly comparing monthly to TREX dosing for neovascular AMD management. Through year 2, monthly and TREX dosing using ranibizumab (Lucentis, Genentech, South San Francisco, CA) achieved similar visual and anatomic outcomes with a significantly reduced treatment burden with TREX dosing.15 16 The goals of the third year of TREX-AMD were to evaluate outcomes following (1) transition of monthly subjects to PRN, and (2) transition of TREX subjects to PRN after achieving a 12-week dosing interval. The current manuscript describes outcomes of the TREX-AMD trial through its final, third year.

    Methods

    TREX-AMD was a prospective, phase IIIb, multicentre, randomised, clinical trial (US Food and Drug Administration Investigational New Drug 116786, NCT01748292).15 16 Institutional Review Board approval was obtained, all subjects signed written, informed consent, and all study procedures adhered to the tenets set forth in the Declaration of Helsinki and the Health Insurance Portability and Accountability Act. Data were collected at Retina Consultants of Houston (Houston, Katy, and Woodlands, Texas) and Palmetto Retina Center (West Columbia, South Carolina). Detailed study methods have been previously reported.15 16 Briefly, 60 subjects with treatment-naïve neovascular AMD were randomised 1:2 to Monthly or TREX cohorts following informed consent. All subjects received 0.05 mL intravitreal injections of ranibizumab (0.5 mg) administered monthly (28±7 days) for three treatments. Subjects in the TREX cohort (n=40) had their treatment individualised based on exudative disease activity.15 16 The maximum interval between treatments was 12 weeks. A macula transitioned from ‘wet’ to ‘dry’ upon resolution of intraretinal and subretinal fluid on spectral-domain optical coherence tomography (SD-OCT) with no haemorrhage visible by ophthalmoscopy.

    Upon completion of year 2 and initiation of year 3, management strategies for the two cohorts changed. In the third year of the trial, subjects initially randomised to the Monthly cohort were evaluated monthly and only retreated upon evidence of exudative disease activity (PRN); subjects initially randomised to TREX dosing were continued on TREX dosing if the interval between visits was less than 12 weeks, or transitioned to PRN after maintaining a dry macula at an interval of 12 weeks between visits. In the current manuscript, for patients in the TREX cohort, best corrected visual acuity (BCVA) and central retinal thickness (CRT) presented for years 1 and 2 are illustrated using data from the visit closest to weeks 26, 52, 78 and 104; if two visits were equidistant from one of these time points, the visit with higher BCVA or lower CRT was used. BCVA and CRT data during year 3 are presented on a 4-week basis for all subjects. Visits for subjects who remained on a TREX regimen were grouped by consecutive 4-week intervals to fit within this scheme; for the final, year 3 data point, data from the final clinical visit were used. Year 3 injection data represent injections administered from week 104 to week 156, inclusive of week 104 and not inclusive of week 156, as no subjects were eligible for study injection at week 156. For subjects transitioning from TREX to PRN, only injections administered during the PRN period were included in the assessment of injection frequency.

    Sample size was a key limitation of the TREX-AMD study. At study initiation, an enrolment of 60 subjects gave 42% power to detect non-inferiority of TREX to Monthly dosing with a non-inferiority margin of five ETDRS letters,15 and a total of 177 subjects randomised 1:2 would have been required to achieve 80% power. In order to mitigate these issues and maximise sample size, intention-to-treat analyses were conducted using last observation carried forward method to include the 14 subjects who did not complete year 3 (n=2 (Monthly); n=12 (TREX)). Proportions of subjects gaining or losing 15 or more ETDRS letters were defined at month 36 (M36) and included subjects who dropped out of the trial before this time point but achieved the defined milestones. An area under the curve (AUC) analysis of BCVA, representing the letter change for each subject averaged over each follow-up visit through 3 years, was also performed; this measure was calculated by determining the AUC for BCVA change from baseline via the trapezoid rule and dividing by the number of weeks from baseline to exit; only subjects who completed year 3 were included in this analysis (n=46). Categorical variables were compared using the χ2 test and continuous variables were compared using the unequal variance t-test or analysis of variance followed by Tukey’s test, as appropriate. Statistical comparisons were performed using R version 3.3.1 (R Project for Statistical Computing, Vienna, Austria, www.r-project.org).

    Results

    Sixty eyes with neovascular AMD with ETDRS BCVA between 78 and 18 (20/32–20/500 Snellen equivalent) from 60 subjects were initially randomised to Monthly (n=20) and TREX (n=40) cohorts. Of the 50 (83%) subjects completing month 24 (M24), 46 (92%) subjects completed M36, yielding a 3-year completion rate of 77% (46/60). During year 3, four subjects withdrew or were lost to follow-up due to death (n=2), cerebral vascular accident (n=1) and severe pulmonary disease (n=1). BCVA and anatomic outcomes are illustrated in figures 1 and 2.

    Figure 1
    Figure 1

    Graph of mean change in ETDRS BCVA through year 3. Error bars represent ±SE of the mean. BCVA, best corrected visual acuity; PRN, pro re nata; TREX, treat and extend. 

    Figure 2
    Figure 2

    Graph of mean central retinal thickness through year 3. Error bars represent ±SE of the mean. PRN, pro re nata; TREX, treat and extend.

    Outcomes among subjects transitioned from Monthly to PRN

    Following transition from monthly dosing to PRN retreatment, the visual gains maintained through 2 years appeared to decline. Mean change in BCVA decreased from +10.5 letters at M24 to +5.4 letters at M36, a loss of 5.1 mean letters (p=0.09). Subjects achieving 10 and 15 letter gains were observed in 8 (40%) and 3 (15%) subjects, respectively, at M36 compared with baseline. Upon transition to PRN dosing at M24, a mild increase in mean CRT ranging from +1 µm to +20 µm was observed at each subsequent visit through M36. Three (15%) subjects required no dosing through the third year while the remaining 17 (85%) subjects received between 1 and 13 injections. Of a total 243 possible PRN injections, 114 (47%) were administered, yielding a mean of 6.1 and a median of 5.5 injections during year 3 (table 1).

    View this table:
    Table 1

    Treatment frequencies in year 3 of TREX-AMD

    Outcomes among subjects continued on TREX

    Beginning in year 3, subjects initially randomised to TREX were divided into two groups based on the interval between treatments. The subjects who did not achieve the maximum 12-week interval between treatments were maintained on the original TREX protocol (n=21). With continued TREX dosing, BCVA outcomes remained relatively stable, with a change of −1.8 mean letters compared with M24 (p=0.11), resulting in an overall mean change from baseline of +5.0 letters at M36. Subjects achieving 10 and 15 letter gains were observed in 13 (42%) and 10 (32%) subjects, respectively, at M36 compared with baseline. Mean CRT remained stable through the third year. A mean of 9.2 and a median of 9 injections were administered during year 3 (table 1). Among the subjects completing M36 (n=20), six (30%) subjects were at an extension interval of ≥8 weeks, eight (40%) subjects were at a treatment interval <6 weeks, and the mean maximum tolerated extension interval was 8.1 weeks.

    Outcomes among subjects achieving quarterly dosing with TREX

    Nine subjects (23%) among those initially randomised to TREX dosing at the initiation of the TREX-AMD trial achieved an interval between injections of 12 weeks and transitioned to PRN retreatment in year 3. This subgroup appeared to display a notably inferior BCVA trajectory compared with both of the other groups (ie, initial Monthly cohort, and subgroup continued on TREX) throughout the entire 3 years. While simple analysis of letter change scores identified no significant differences between mean BCVA changes at M36 among cohorts (p=0.20), analysis of AUC for change in BCVA averaged over 3 years (Monthly: +9.5 letters, continued TREX: +10.4 letters, TREX to PRN: −1.5 letters) revealed significant differences between cohorts (p=0.04). In particular, TREX subjects who transitioned to PRN after achieving 12-week dosing had significantly worse visual outcomes compared with subjects who did not reach the maximum possible extension interval and therefore continued TREX dosing in year 3 (p=0.04). While these TREX to PRN subjects demonstrated a mean gain of BCVA at month 3, from month 12 onwards, the cohort demonstrated a loss of BCVA: −5.0 mean letters at M24 and −6.7 mean letters at M36. Visual losses were driven by three subjects, with changes of −12, –42 and −45 letters due to subretinal fibrosis for the first and macular atrophy for the latter two. Six subjects gained BCVA at M36 compared with baseline, with just one subject (11%) gaining at least 10 letters. Within this subgroup, the need for ongoing anti-VEGF retreatments during the third year was small, with four intravitreal injections being delivered among 106 (4%) PRN evaluation visits. These treatments were isolated to two (22%) subjects, who demonstrated gains of +4 and +17 letters at M36 compared with baseline; the remaining seven (78%) subjects required no anti-VEGF dosing during year 3.

    Adverse events

    Across the entire 3-year TREX-AMD trial no new safety signals were identified; two (10%) subjects initially randomised to Monthly and six (15%) subjects initially randomised to TREX experienced a serious ocular adverse event including retinal pigment epithelium tear (n=1), progressive macular atrophy (n=3), serious subretinal haemorrhage (n=3) and Hollenhorst plaque (n=1). Seven (35%) subjects initially randomised to Monthly and 20 (50%) subjects initially randomised to TREX experienced a systemic serious adverse event including death (n=3). No cases of endophthalmitis or intraocular inflammation were identified among 1456 total injections.

    Discussion

    Multiple large, well-powered, prospective trials evaluating PRN management of neovascular AMD have reported that less than 10% of subjects may not require ongoing anti-VEGF dosing upon achieving a dry macula, at least within 2 years of follow-up.4 21 22 The current analysis identified a similar proportion of subjects, 15%, not requiring additional dosing upon transition to PRN dosing after 2 years of fixed monthly dosing.

    Furthermore, when internally compared with a fixed monthly dosing arm, large PRN trials have reported that visual outcomes with PRN dosing are slightly less favourable by about two mean letters.4 5 While the importance or relevance of two letters difference can and should be debated, there appears to be a reproducible difference in outcomes between PRN dosing and fixed monthly dosing. The current analysis identified a similar trajectory of visual decline upon transition from monthly to PRN dosing, even after 2 years of fixed monthly treatments. Such findings may indicate that longer duration anti-VEGF agents or sustained release devices that minimise recurrences of exudative disease activity may facilitate optimal outcomes.

    In the current analysis, the majority (78%, n=31) of subjects initially randomised to TREX did not achieve the maximum possible interval between treatments of 12 weeks through 2 years of management, and required ongoing, more frequent dosing to maintain a dry macula. Conversely, 23% (n=9) of TREX subjects did achieve the predefined maximum extension interval of 12 weeks by M24. Currently, there are limited data to guide the management of neovascular AMD subjects treated with TREX who appear clinically stable and have no evidence of exudative disease activity by examination or SD-OCT at a 12-week interval. In the current series, two findings were evident among this population. First, the need for repeated intravitreal injections was minimal through one additional year of follow-up, with 96% of possible PRN injections not being delivered. Nevertheless, two subjects (22%) did require retreatment due to recurrent exudative disease activity, indicating that long-term close clinical follow-up is required, even among eyes demonstrating minimal exudative disease activity. Imaging approaches such as OCT angiography that may be able to distinguish subjects who require ongoing dosing from those who do not may be clinically valuable.23 Second, as a population, subjects who achieved a 12-week interval between treatments using TREX with no evidence of active exudative disease lost BCVA from baseline through 1, 2 and 3 years of dosing with a subset of subjects demonstrating particularly poor outcomes due to loss of foveal function secondary to fibrosis and macular atrophy.24 Thus, the poor outcomes in these particular subjects may not necessarily be related to undertreatment, but rather, these eyes which do not manifest ongoing choroidal neovascularisation activity could possibly be severely impaired and perhaps prone to develop atrophy. Despite these remarkably poor outcomes, it should be noted that the majority of this subgroup (67%, n=6) did not lose vision through 3 years.

    The strength of the current study is its multicentre, prospective design with good protocol compliance. The key limitation is the small population analysed through 3 complete years. Longer term follow-up of neovascular AMD management is challenging for many reasons. Subject attrition is a reality of any prospective trial especially in an elderly population. Among the current dataset of the 23% who did not complete 3 years, 21% had died and 43% were unable to return to clinic due to disabling serious systemic adverse events. Additionally, more adequately powered long-term investigations are warranted to corroborate the present findings.

    In summary, minimisation of episodes of recurrent exudative disease activity likely optimises ultimate VA outcomes in the long-term management of neovascular AMD, and utilisation of a TREX approach in the management of neovascular AMD requires ongoing close clinical care even among subjects who appear to have quiescent exudative disease activity at quarterly dosing.

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    Footnotes

    • Contributors Research design: CCW, DEC, DMB. Data acquisition and/or research execution: CCW, WCO, DEC, JFP, DMB, WLC. Data analysis and/or interpretation: CCW, WCO, DEC, NSA, SRS. Manuscript preparation: CCW, WCO, DEC, JFP, DMB, WLC, NSA, SRS.

    • Funding Research grant from Genentech, Inc., South San Francisco, CA. The funding organisation 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 Genentech, Inc., South San Francisco, CA; 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. JFP reports grants from Genentech, grants from Regeneron, grants from Alcon, grants from EMMES, grants from Bayer, personal fees from Adverum, grants and personal fees from Allergan, grants and personal fees from DRCR Network. DMB reports grants and personal fees from Regeneron, 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, 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, grants, personal fees and non-financial support from Regeneron Pharmaceuticals. SRS reports other from Topcon, grants and personal fees from Carl Zeiss, grants and personal fees from Optos, personal fees from Allergan, personal fees from Iconic Therapeutics, personal fees from Novartis, personal fees from Thrombogenics, grants and personal fees from Genentech. No other relationships or activities could appear to have influenced the submitted work.

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

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

    • Collaborators Members of the TREX-AMD Study Group: CCW, WCO, DEC, JFP, DMB, WLC, NSA, SRS, Matthew S Benz, Eric Chen, Richard H Fish, Christopher R Henry, David L Johnson, Rosa Y Kim, James C Major Jr., Ronan E O’Malley, Amy C Schefler, Ankoor R Shah, Rui Wang, John A Wells III, Tien P Wong