Comparison of Two Different Treat-and-Extend Protocols with Aflibercept in Wet Age-Related Macular Degeneration: Two-Year Results

EU Clinical Trials Register Number: 2015-001394-41/FI | | Taipale C et al. (2020) – Two-year

Taipale C, Lindholm J-M, Kaarniranta K, Tuuminen R. Comparison of Two Different Treat-and-Extend Protocols with Aflibercept in Wet Age-Related Macular Degeneration: Two-Year Results. Adv Ther, 2020; 37:2256–2266.

Locations

Single-center study in Finland

Study Period

January 2016 – July 2017

Study Design

Prospective, randomized, open-label, single-center study

Study Population

Characteristic:

Type of AMD:

Wet

AMD Stage:

3 (Late)

Total Sample Size:

52 patients (26 in T&Em, 26 in T&Er)

Age:

Prospective, randomized, open-label, single-center study

Sex (Male) n%:

18 (34.6%) (derived from group distributions)

Experimental Group

Intervention Therapy:

Aflibercept 2 mg Treat-and-Extend with Moderate Extensions (T&Em)

Dose & Frequency:

Three loading doses, then extended by 1 week at a time up to 12 weeks, then by 2 weeks up to 16 weeks

Age (Years):

76.3 ± 8.5

Number of Patients:

26 randomized and treated

Male N %:

9 (34.6%)

Patients Followed Up:

24 (92.3%)

Control Group

Intervention Therapy:

Aflibercept 2 mg Treat-and-Extend with Rapid Extensions (T&Er)

Dose & Frequency:

Three loading doses, then directly extended to 8 weeks, then by 2 weeks up to 16 weeks

Age (Years):

76.6 ± 6.9

Number of Patients:

26 randomized and treated

Male N %:

9 (34.6%)

Patients Followed Up:

24 (92.3%)

Follow-up Time: 24 months

Outcomes

Durability

Treatment Interval The mean ± SD treatment interval at 24 months (weeks):
• T&Em: 10.3 ± 3.3
• T&Er: 11.7 ± 3.5
• Difference: p = 0.164 Number of Injections Total mean ± SD number of injections over 24 months:
• T&Em: 14.1 ± 3.1
• T&Er: 11.6 ± 2.0
• Difference: p = 0.002 Number of injections in Year 2:
• T&Em: 5.4 ± 1.8
• T&Er: 4.4 ± 1.4
• Difference: p = 0.043 The mean number of injections at 2 years was lower in the T&Er group than in the T&Em group (difference - 2.5 injections, 95% CI - 1.0 to - 4.0, P = 0.002)

Vision

Best-Corrected Visual Acuity (BCVA) The mean ± SD change in BCVA (ETDRS letters) at 24 months (primary outcome):
• T&Em: +7.9 ± 14.5
• T&Er: +10.8 ± 16.5
• Difference: p = 0.726 The mean ± SD in BCVA (ETDRS letters) at 24 months (primary outcome):
• T&Em: 59.3 ± 14.7
• T&Er: 59.1 ± 14.9
• Difference: p = 0.910 Vision Maintaining The proportion of patients gaining ≥15 ETDRS letters:
• T&Em: 3 (13%)
• T&Er: 4 (17%) The proportion of patients gaining ≥10 ETDRS letters:
• T&Em: 4 (17%)
• T&Er: 7 (29%) The proportion of patients gaining ≥5 ETDRS letters:
• T&Em: 6 (25%)
• T&Er: 9 (38%) The proportion of patients change±4 ETDRS letters:
• T&Em: 10 (42%)
• T&Er: 8 (33%) The proportion of patients losing ≥5 ETDRS letters:
• T&Em: 8 (33%)
• T&Er: 7 (29%) The proportion of patients losing ≥10 ETDRS letters:
• T&Em: 3 (13%)
• T&Er: 6 (25%)
• The proportion of patients losing ≥15 ETDRS letters:
• T&Em: 3 (13%)
• T&Er: 2 (8%)

Other

N/A

Immunognicity

Not reported

Pharmokinetics

Not reported

Anatomic

Retinal Fluid Patients achieved dry macula with no intraretinal or subretinal fluid at 2 years:
• T&Em: 71%
• T&Er: 71%
• Difference: p = 1.000 The time to achieve dry macula:
• T&Em: 22.5 ± 28.8 weeks
• T&Er: 26.4 ± 31.3 weeks
• Difference: p = 0.654 At the baseline and after three monthly aflibercept injections, foveal thickness, CSMT, and maximal macular thickness all correlated with the time to achieve dry macula. Central Subfield Macular Thickness (CSMT) The mean ± SD change in CSMT (µm) at 24 months:
• T&Em: -203.0 ± 167.4
• T&Er: -192.3 ± 160.2
• Difference: p = 0.822 Foveal Thickness The mean± SD change in foveal thickness (µm) at 24 months:
• T&Em: -219.6 ± 188.3
• T&Er: -212.8 ± 174.3
• Difference: p = 0.897

Safety

Ocular AEs Two study eyes were subjected to corneal abrasions during intravitreal injections, but the predetermined treatment intervals were not affected. Serious ocular AEs No serious ocular or systemic adverse events or suspected unexpected serious adverse reactions were observed during the 2-year treatment period. Non-ocular AEs Death One patient died during the 2-year treatment period.

Outcomes

Conclusion

Both aflibercept treat-and-extend protocols resulted in similar visual and anatomical improvements over 2 years. The rapid extension protocol required fewer injections than the moderate extension protocol. No major safety concerns were observed.

Risk of Bias Assessment for Primary Outcome

Randomization Process

Low risk
Note: The method of allocation concealment was not supplied. However, the baseline characteristics of the two groups are comparable.

Missing Outcome Data

Low risk
Note: Four patients (4/52, 7.7%, less than 5% for each group) were excluded from the final analysis. However, the missingness was not depended on true value.

Selection of the Reported Results

Low risk Note: Registration with protocol

Deviations from Intended Observations

Some concerns Note: This is an open-labeled study. However, the paper provided the reasons for those who did not complete the study, which is not because of the trial context (low risk). Four patients (4/52, 7.7%, less than 5% for each group) were excluded from the final analysis (therefore, (m)ITT was not applied). For the primary outcome (the number of injections), there should be no potential impact (some concerns).

Measurement of the Outcome

Low risk Note: For the primary outcome (the number of injections), acknowledge of the intervention should not impact the measurement.

Overall

Some concerns