Age related macular degeneration (AMD)

A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss (AREDS), 2001 ⏩
n=3640 (age 55-80), 6.3y
Study question: AMD patients randomized to tx with either antioxidants (C,E,Beta carotene) VS Zinc with copper VS combination VS placebo.
Study results: Defined severity of AMD (Intermediate - extensive intermediate size drusen, at least 1 large druse, noncentral geographic atrophy in 1 or both eyes). Found significant odds reduction for the development of advanced AMD in the combination group (odds ratio 0.72), zinc alone (0.75)  antioxidants alone (0.80). Greater effect when excluding the Early AMD group (combination odds ratio 0.66, zinc 0.71, antioxidants 0.76). Significant reduction in moderate VA loss occurred only in the combination group (OR, 0.73). Smoking is a contraindication for beta-carotene supplements d/t risk of cancer and genitourinary complaints. See AREDS2.



Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2), 2005 ⏩
n=1608, 5y
In light of AREDS study (see above) looking for an alternative formulation with less side effects. Study question: AMD patients treated with AREDS vitamins formula VS formula w\o beta-carotene VS low zinc dose VS no zinc and no beta-carotene. These groups were randomized for an alternative  supplementation of: lutein+zeaxanthin VS DHA (docosahexaenoic acid) + EPA (eicosapentaenoic acid) VS combination VS placebo.  Study results: More lung cancers in the beta carotene group (2.0% vs 0.9%), mostly in former smokers. No apparent effect of beta carotene elimination or lower-dose zinc on progression to advanced AMD. Reduction of progression to advanced AMD similar across alternative supplement groups.


Risk of advanced age-related macular degeneration after cataract surgery in the Age-Related Eye Disease Study: AREDS report 25, 2005  ⏩
n=4577,  9.5y
Study question: Post hoc analysis of the AREDS cohort. Does cataract surgery affect risk for AMD progression? Study results: AREDS data suggest that there is no clinically important increased risk of progression to advanced AMD following cataract surgery.


Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration (PIER), 2008 ⏩ and another link ⏩
N=182, 24m
Phase 3b, multicenter, randomized, controlled trial. Sham VS Ranibizumab monthly injections for 3 months and then quarterly. 90% in the group receiving the 0.5 dose lost <15 letters compared with 49% in the sham group; 13% versus 10% gained >15 letters.73 As the overall VA, returned to baseline from month 3 to month 12 after switching to Q3M. Quarterly dosing is inferior to monthly dosing. This was subsequently confirmed by the EXCITE study (see below).

A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study, 2009 ⏩
Open-label, prospective, single-center, uncontrolled clinical study
N=40, 2y
Ranibizumab PRN guided by OCT is effective. Follow-up Monthly Mean VA +11 letters. Similar studies: SAILOR, SUSTAIN.

Ranibizumab for neovascular age-related macular degeneration (MARINA), 2006 ⏩
N=415, 2y
Minimally classic or occult CNV. 24 monthly inj. 0.3 or 0.5 mg of ranibizumab or sham.
At 12 months, 95% of ranibizumab-treated eyes compared with 62% of sham-treated eyes, lost <15 letters. At 24m: 90% of eyes in the 0.5 mg group had continued to maintain stable vision without loss of >15 letters compared with 53% in the control group. Dosage 0.3 = 0.5mg

Anti-vascular endothelial growth factor (VEGF) Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization (CNV) in Age-related Macular Degeneration (ANCHOR), 2009  ⏩
N=423, 2y
Classic subfoveal CNV
24 Monthly injections of ranibizumab at 0.3 or 0.5 mg were compared with standard PDT at 3m intervals. VA improved by 8.1 to 10.7 letters vs. a mean decline of 9.8 letters in PDT group. Dosage of 0.3 comparable to 0.5

Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study, 2011 ⏩
N=293, 24m
Study question: Further establish PIER results (see above): 0.3 mg quarterly, 0.5 mg quarterly, or 0.3 mg monthly of ranibizumab. Results: After 3 initial monthly ranibizumab injections. At month 12, BCVA gain in the monthly regimen was higher than that of the quarterly regimens.

Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results (CATT), 2012 ⏩ and ⏩
N=1107, 2y
Study question: Avastin VS Lucentis, both PRN VS Monthly.
Study Results: Not a significant advantage for Lucentis. Monthly had more stable and significantly better VA (2.4 letters). More patients with 3 line vision loss in PRN (12% vs 7% for q1m). Eyes on q1m that switched to RPN lost 1.5-3 letters. More Geographic atrophy in monthly tx. No commercial financial support. Slightly more systemic side effects for Bevacizumab (See IVAN).

Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the (IVAN) randomized trial, 2012 ⏩
N=610, 1y
Study Question: Bevacizumab VS  Ranibizumab. Monthly or PRN.
Study Results: No advantage for PRN, no difference between drugs. In case of a recurrence patients got a set of 3 injections-not just 1 like in CATT. Slightly more systemic side effects for Bevacizumab (see CATT)

Open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration (HORIZON), 2012  ⏩
n=850, 4y
Study question: RNZ 0.5 PRN after MARINA,ANCHOR FOCUS. Study results:  Results-lost 8 letters once the switched from q1m to PRN. m/p because no fixed protocol and mean of 3.6 RNZ in the 12m. Safety was the main outcome.

Twelve-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration (HARBOR), 2013 ⏩
n=1098, 24m
Study question: Efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg q1m vs PRN for naïve patients with sub-foveal CNV d/2 AMD. Study results: PRN groups requiring 8 fewer inj than q1m with similar final VA gains. 2mg similar to 0.5mg, including safety but not approved for clinical use.


Ranibizumab versus Bevacizumab for Neovascular Age-related Macular Degeneration: Results from the GEFAL Noninferiority Randomized Trial, 2013 ⏩
n=501, 1y
Study question: Bevacizumab (1.25 mg) VS Ranibizumab (0.50 mg) for NVAMD. 3 mandatory inj then PRN. Study results: bevacizumab was noninferior to ranibizumab in letter gain (BCVA difference -1.89 letters in Avastin), # of injection (6.8 vs 6.5), CMT inprovment (95 micron vs 107), serious adverse events or systemic adverse events.


Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies (VIEW 1, VIEW 2), 2014 ⏩
n=2457, 96w
Study question: Extension of VIEW1 and VIEW2 - 4 arms: Ranibizumab q1m 0.5mg vs Aflibercept q1m (2mg or 0.5mg) vs 2mg q8w with 3 mandatory q1m then q2m. After 52 weeks all groups changed to PRN with mandatory inj every 3m.  Study results:  When changed to PRN majority of patients retained BCVA (~91%) but less eyes "dry retina" (60.3% to 44% and 72.4% to 54%). Mean BCVA gains were 8.3 to 9.3 letters at week 52 and 6.6 to 7.9 letters at week 96. Mean # inj 16.5, 16.0, 16.2, and 11.2 (Ranibizumab q4w, 2mg q4w, 0.5mg q4w, and 2mg q8w). 51% maintained VA under aflibercept q3m. The 2mg q8w aflibercept group was similar to ranibizumab in visual acuity outcomes during 96 weeks, but with an average of 5 fewer injections. Antiplatelet Trialists' Collaboration-defined arterial thromboembolic events were similar across groups. $ by Regeneron and Bayer 



Ranibizumab or Bevacizumab for Neovascular Age-Related Macular Degeneration According to the Lucentis Compared to Avastin Study Treat-and-Extend Protocol: Two-Year Results (LUCAS), 2016 ⏩
n=441, 2y
Study question: Treat and extend of bevacizumab versus ranibizumab for neovascular age-related macular degeneration (nAMD). Study results: bevacizumab was equivalent to ranibizumab, with 7.4 and 6.6 letters gained, respectively. No difference in CMT. Significantly less injections (16) of ranibizumab versus bevacizumab (18.2).




Two Different Treat and Extend Dosing Regimens of Intravitreal Afibercept for wAMD in Japanese Patients: 52 Week Results (ALTAIR Study), 2017 ⏩ see also summary of T&E studies
n=247, 52w
Study question: Aflibercept Treat and extend with 2w intervals vs 4w intervals of for NVAMD after 3 mandatory q1m inj. Study results: 2w interval gained a mean of 9 EDTRS letters VS 8.4 for the 4w. 32% gained 15 or more letters within a year in 2w versus 30.9% in the 4w interval. 2w had mean inj # of 7.2 VS  6.9 inj  in 1 year. q12w interval maintained VA for 42% of the 2w interval and 49% of the 4w interval.



RIVAL study (EURETINA 2017) ⏩
n=278, 1y on going to 2y
Study question: T&E - Lucentis 0.5 mg Vs Aflibercept 2.0 mg
Study Results: At 1 year, Mean ETDRS letter gained: Lucentis  7.1 vs 4.9 letter gain in the aflibercept group.


Randomized Trial of Treat-and-Extend versus Monthly Dosing for Neovascular Age-Related Macular Degeneration 2-Year Results (TREX-AMD Study), 2017 ⏩
n=60, 2y
Study question: 0.5 mg ranibizumab monthly Vs TREX protocol
Study results:  ETDRS BCVA letter gains were similar: 10.5 for q1m, and 8.7 for TREX. Mean number of injections administered was 25.5 (range, 22–27) and 18.6 (range, 10–25)


Aflibercept as a Second Line Therapy for Neovascular Age Related Macular Degeneration in Israel (ASLI) study, 2017 ⏩
n=46, 28w
Study question: Incomplete response to 3–9 prior bevacizumab injections treated with 3 q1m  aflibercept, then 2 q2m. Study results: improved VA and reduced CST following an early switch to aflibercept therapy in eyes with prior incomplete response to initial therapy with 3-9 bevacizumab injections.


Brolucizumab Versus Aflibercept in Participants with Neovascular Age-Related Macular Degeneration: A Randomized Trial (OSPREY), 2017 ⏩
n= 89, 56w
Study Question: Brolucizumab (6 mg/50 μl) VS Aflibercept for NVAMD. 3 monthly inj then q8w.
Study results: brolucizumab group gained 5.75 letters vs 6.89. Brolucizumab had fewer unscheduled treatments (6 vs. 15) . ~50% of brolucizumab group had stable BCVA during the q12 cycles. Safety profile similar.


Treat-and-Extend versus Monthly Regimen in Neovascular Age-Related Macular Degeneration (TREND), 2018 ⏩
n=650, 12m
Study question: naïve nAMD patients (age, ≥50 years) were randomized 1:1 to receive either a ranibizumab 0.5 mg T&E (n = 323) Vs monthly (n = 327)
Study results: Mean ETDRS letter gain was 6.2 for T&E vs 8.1 for monthly tx - statistically noninferior. Fewer injections in the T&E (8.7) versus monthly (11.1), with mean number of postbaseline visits of 8.9 and 11.2, respectively. Most BCVA improvements occurred during the first 6 months and were maintained until the end of the study.


Tolerating Subretinal Fluid in Neovascular Age-Related Macular Degeneration Treated with Ranibizumab Using a Treat-and-Extend Regimen: FLUID Study 24-Month Results (FLUID Study), 2019  ⏩ and ⏩

n=349, 2y
Study Question: Ranibizumab 0.5 mg q1m T&E. Intensive arm: SRF intolerant or Relaxed arm: SRF tolerant except for SRF >200 μm at the foveal center. 

Study Results: The mean change in BCVA was 3.0 in the intensive VS 2.6 letters in the relaxed group. Relaxed group received mean 15.8 inj VS 17 in the intensive. 13.%  of the intensive group never extended beyond 4-week vs 2.8%. 29.6% of the relaxed group VS 15% extended to and maintained 12-week treatment interval. Note: CATT and HORIZON showed that BCVA was associated with higher # of inj. And post hoc analysis of CATT, IVAN, HAWK, HARRIER studies did show that higher CST variability was associated with worse BCVA. 

HAWK and HARRIER: Phase 3, Multicenter, Randomized, Double-Masked Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration, 2019  ⏩
HAWK n=1082, 2y
Study question: HAWK brolucizumab 3 mg VS brolucizumab 6 mg, VS aflibercept 2 mg. 3 loading inj then q12w or q8w if active. Study Results: BCVA change from baseline +6.6 [6 mg] and +6.1 [3 mg] letters with brolucizumab vs. +6.8 letters with aflibercept.
56% of the  6 mg–treated eyes were maintained on q12w dosing through Week 48. At Week 16, after identical treatment exposure, 24% brolucizumab 6 mg–treated eyes had disease activity versus 34% aflibercept patients.
HARRIER n=743, 2y
Study Question HARRIER: brolucizumab 6 mg VS aflibercept 2 mg for NVAMD. 3 loading inj then q12w or q8w if active.  Study results: +6.9 [brolucizumab 6 mg] vs. +7.6 [aflibercept].
51% of brolucizumab 6 mg–treated eyes were maintained on q12w dosing.

Please also note postmarking concerns of drug induced sight threatening ocular inflammation were later discussed in several studies ($ by Novartis).


Intravitreal Aflibercept Injection vs Sham as Prophylaxis Against Conversion to Exudative Age-Related Macular Degeneration in High-risk Eyes: A Randomized Clinical Trial (PROCON Trial), 2021 ⏩

n=128, 2y

Study Question: q3m Aflibercept VS sham for intermediate high risk AMD (and exudative AMD in the fellow eye)

Study result: Conversion to exudative AMD was 9.5% in the Aflibercept group VS 10.9% in the sham group (P = .98).

Phase III, Multicenter, Randomized, Visual Assessor-Masked, Active-Comparator Study of the Efficacy, Safety, and Pharmacokinetics of the Port Delivery System With Ranibizumab in Patients With Neovascular Age-Related Macular Degeneration (ARCHWAY) Presented, unpublished ⏩ and ⏩ or ⏩

n=418, 40w

Study question: ranibizumab delivered through the PDS implant with 100 mg/mL q24w VS ranibizumab q1m. Study results: 98% of patients in the PDS arm did not need rescue injections until the 6m refill appointment. 

$ Hoffmann-La Roche

Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration: two randomised, double-masked, phase 3, non-nferiority trials (TENAYA and LUCERNE), 2022 ⏩

TENAYA n=671, LUCERNE n=658, 112w, endpoint 52w.

Study question: faricimab 6mg (4 monthly then tx at fixed intervals of 8w\12w\16w) compared to aflibercept 2mg- 3 monthly injections then q8w. Second year: T&E 4w steps) Study results: 50% of the faricimab patients were dry at q16w interval. ~80% in both studies were treated at 12 weeks or longer. Overall, Faricimab was non-inferior to Aflibercept in averaged change in VA VA gained (5.1 to 6 letters). Intra-ocular inflammation was 2% versus 1.2% for aflibercept) and APTC events were comparable. Open label extension study: AVONELLE X ($ Roche)

Abbreviations on this page:
$ - Study funding, when relevant

APTC - Anti-Platelet Trialists’ Collaboration
BCVA - Best corrected visual acuity
CNV - Choroidal neovascularization
d/2 - due to
inj - injections

IOI - intra ocular inflammation
m - months
OCT - optical coherence tomography
PDT - Photo-dynamic therapy
PRN - Pro re nata (as needed with monthly visits)
Q3M - Treat once in 3 months
VA - visual acuity
VEGF - Anti-vascular endothelial growth factor

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⭐Additional information can be found on Eyewiki's section on Aflibercept.
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