Eylea 40 mg/ml solution for injection in a vial

  • Name:

    Eylea 40 mg/ml solution for injection in a vial

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  • Active Ingredients:

    Aflibercept

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    Product subject to medical prescription which may not be renewed (A)

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Bayer Limited

Bayer Limited

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 29 January 2019 Ed-HCP

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Updated on 7 August 2018 PIL

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Updated on 7 August 2018 SmPC

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In Section 4.2 - The posology for neovascular (wet) age-related macular degeneration (AMD) has been updated and the treatment duration extended.

In the section "Method of Administration" - Addition of "Extraction of multiple doses from a single vial may increase the risk of contamination and subsequent infection.

In section 5.1 - Addition of: The ALTAIR study was conducted in Japanese patients with treatment naïve wet AMD, showing similar outcomes to the VIEW studies using 3 initial monthly Eylea 2 mg injections, followed by one injection after a further 2 months, and then continued with a treat-and-extend regimen with variable treatment intervals (2-week or 4-week adjustments) up to a maximum 16 week interval according to pre-specified criteria. At week 52, there were mean decreases in central retinal thickness (CRT) on OCT of -134.4 and –126.1 microns for the 2-week adjustment group and the 4-week adjustment group, respectively. The proportion of patients without fluid on OCT at week 52 was 68.3% and 69.1% in the 2- and 4-week adjustment groups, respectively.

 

......

ALTAIR is a multicentre, randomised, open-label study in 247 Japanese patients with treatment naïve wet AMD, designed to assess the efficacy and safety of Eylea following two different adjustment intervals (2-weeks and 4-weeks) of a treat-and-extend dosing regimen.

 

All patients received monthly doses of Eylea 2 mg for 3 months, followed by one injection after a further 2 month interval. At week 16, patients were randomised 1:1 into two treatment groups: 1) Eylea treat-and-extend with 2-week adjustments and 2) Eylea treat-and-extend with 4-week adjustments. Extension or shortening of the treatment interval was decided based on visual and/or anatomic criteria defined by protocol with a maximum treatment interval of 16 weeks for both groups.

 

The primary efficacy endpoint was mean change in BCVA from baseline to week 52. The secondary efficacy endpoints were the proportion of patients who did not lose ≥15 letters and the proportion of patients who gained at least 15 letters of BCVA from baseline to week 52.

At week 52, patients in the treat-and-extend arm with 2-week adjustments gained a mean of 9.0 letters from baseline as compared to 8.4 letters for those in the 4-week adjustment group [LS mean difference in letters (95% CI): -0.4 (-3.8,3.0), ANCOVA]. The proportion of patients who did not lose ≥15 letters in the two treatment arms was similar (96.7% in the 2-week and 95.9% in the 4-week adjustment groups). The proportion of patients who gained ≥15 letters at week 52 was 32.5% in the 2-week adjustment group and 30.9% in the 4-week adjustment group. The proportion of patients who extended their treatment interval to 12 weeks and beyond was 42.3% in the 2-week adjustment group and 49.6 % in the 4-week adjustment group. Furthermore, in the 4-week adjustment group 40.7% of patients were extended to 16 week intervals. At the last visit prior to week 52, 56.7% and 57.8% of patients in the 2-week and 4-week adjustment groups, respectively had their next injection scheduled at an interval of 12 weeks or more. Ocular and systemic safety profiles were similar to the safety observed in the pivotal studies VIEW1 and VIEW2.

In the section "Information for Healthcare Professionals", addition of: "Extraction of multiple doses from a single vial may increase the risk of contamination and subsequent infection. "

Updated on 18 August 2017 SmPC

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Updated on 18 August 2017 SmPC

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In Section 5.1 -  Minor typographical updates

In Section 6.4 - minor wording update to storage conditions

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In section 10- Date of revision of the text has been updated to 07/2017

Updated on 16 August 2017 PIL

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Updated on 16 August 2017 PIL

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Updated on 22 May 2017 PIL

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Updated on 31 August 2016 SmPC

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Updated on 12 July 2016 PIL

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Updated on 12 July 2016 SmPC

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In 4.2       Posology and method of administration

Posology

wet AMD

 


After the first 12 months of treatment with Eylea, and based on visual and/or anatomic outcomes, the treatment interval may be extended, such as with a treat-and-extend dosing regimen, where the treatment intervals are gradually increased to maintain  stable visual and/or anatomic outcomes;however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly.

 

 The schedule for monitoring should therefore be determined by the treating physician and may be more frequent than the schedule of injections - was inserted.

Under: Diabetic macular oedema

After the first 12 months of treatment with Eylea, and based on visual and/or anatomic outcomes, the treatment interval may be extended, such as with a treat-and-extend dosing regimen, where the treatment intervals are gradually increased to maintain  stable visual and/or anatomic outcomes; however there are insufficient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly.

 

The schedule for monitoring should therefore be determined by the treating physician and may be more frequent than the schedule of injections -was inserted.

Under: Paediatric population

 

The safety and efficacy of Eylea have not been established in children and adolescents. There is no relevant use of Eylea in the paediatric population for the indications of wet AMD, CRVO, BRVO, DME and myopic CNV -was inserted.

Under: Method of administration

 

For handling of the medicinal product before administration, see section 6.6.

In Section: 4.8 Undesirable effects

Description of selected adverse reactions

 

Arterial thromboembolic events (ATEs) are adverse events potentially related to systemic VEGF inhibition. There is a theoretical risk of arterial thromboembolic events, including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors.

A low incidence rate of arterial thromboembolic events was observed in the Eylea clinical trials in patients with AMD, DME, RVO and myopic CNV. Across indications no notable difference between the groups treated with aflibercept and the respective comparator groups were observed -was inserted.

ATEs, as defined by Antiplatelet Trialists’ Collaboration (APTC) criteria, include nonfatal myocardial infarction, nonfatal stroke, or vascular death (including deaths of unknown cause).
The incidence of ATEs in the phase III wet AMD studies during the 96 weeks study duration was 3.3% (60 out of 1,824) in the combined group of patients treated with Eylea compared to 3.2% (19 out of 595) in patients treated with ranibizumab (see section 5.1) The corresponding numbers in the DME studies during the first 100 weeks were 6.4% (37 out of 578) (Eylea) and 4.2% (12 out of 287) (control group) (see section 5.1).
The incidence of ATEs in the phase III CRVO studies during the 76/100 weeks study duration was 0.6% (2 out of 317) in patients treated with at least one dose of Eylea compared to 1.4% (2 out of 142) in the group of patients receiving only sham treatment (see section 5.1) whilst for the Phase III BRVO study during the 52 weeks study duration it was 0% (0 out of 91) in patients treated with Eylea compared with 2.2% (2 out of 92) in the control group (see section 5.1). One of these patients in the control group had received Eylea rescue treatment.
The incidence of ATEs in the myopic CNV study during the 48 weeks study duration was 1.1% (1 out of 91) (Eylea) compared to 0% (0 out of 31) (control group).
-was deleted.

Under:  5.1     Pharmacodynamic properties

 

In patients treated with 6 consecutive monthly injections of Eylea 2mg, there was a consistent, rapid and robust morphologic response (as measured by improvements in mean CRT) observed. At week 24, the reduction in CRT was statistically superior versus control in all three studies (COPERNICUS in CRVO: -457 vs. -145 microns; GALILEO in CRVO: -449 vs. -169 microns; VIBRANT in BRVO: -280 vs. -128 microns) -was inserted.

In the COPERNICUS and GALILEO studies (CRVO) the mean decrease from baseline in CRT at week 24 was significantly greater in patients treated with Eylea 2 mg every month than in the control group (-457 microns vs. -145 microns in COPERNICUS, and -449 microns vs. -169 microns in GALILEO).
In the VIBRANT study (BRVO) the mean decrease from baseline in CRT at week 24 was significantly greater in patients treated with Eylea 2 mg every month than in the control group (-280 microns vs. -128 microns).
This decrease from baseline in CRT was maintained to the end of each study, week 100 in COPERNICUS, week 76 in GALILEO, and week 52 in VIBRANT.
-was deleted.

In patients treated with Eylea in the MYRROR study (one injection given at start of therapy, with additional injections given in case of disease persistence or recurrence), CRT decreased soon after treatment initiation favouring Eylea at week 24 (-79 microns and -4 microns for the Eylea 2 mg treatment group and the control group, respectively), which was maintained through week 48. In addition, the mean CNV lesion size decreased.The mean change in CRT from baseline to week 24 was statistically significant favouring Eylea (-79 microns and -4 microns for the Eylea 2 mg treatment group and the control group, respectively). The decrease from baseline in retinal thickness in the Eylea 2 mg group was maintained through week 48.-was deleted.

The safety and efficacy of Eylea were assessed in two randomised, multi-centre, double-masked, active-controlled studies in patients with wet AMD(VIEW 1 and VIEW 2) with a. A total of 2,412 patients were treated and evaluable for efficacy (1,817 with Eylea) in the two studies (VIEW1 and VIEW2). Patient ages ranged from 49 to 99 years with a mean of 76 years. In these clinical studies, approximately 89% (1,616/1,817) of the patients randomised to treatment with Eylea were 65 years of age or older and approximately 63% (1,139/1,817) were 75 years of age or older. In each study, patients were randomly assigned in a 1:1:1:1 ratio to 1 of 4 dosing regimens: -was deleted.

In Figure 1:

In combined data analysis of the VIEW1 and VIEW2 studies Eylea demonstrated clinically meaningful changes from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25) without clinically meaningful differences to ranibizumab. The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA).

No clinically meaningful differences were found between Eylea and the reference product ranibizumab in changes of NEI VFQ-25 total score and subscales (near activities, distance activities, and vision-specific dependency) at week 52 from baseline.
-was deleted.

In the second year of the studies, efficacy was generally maintained through the last assessment at week 96, and 2-4% of patients required all injections on a monthly basis, and a third of patients required at least one injection with a treatment interval of only one month. -was inserted.

In the second year of the studies, efficacy was generally maintained through the last assessment at week 96.
In the second year of the studies, 2-4% of patients required all injections on a monthly basis, and a third of patients required at least one injection with a treatment interval of only one month.

Elderly Population

In the clinical studies, approximately 89% (1,616/1,817) of the patients randomised to treatment with Eylea were 65 years of age or older and approximately 63% (1,139/1,817) were 75 years of age or older
.-was deleted.

Macular oedema secondary to CRVO

The safety and efficacy of Eylea were assessed in two randomised, multi-centre, double-masked, sham-controlled studies in patients with macular oedema secondary to CRVO (COPERNICUS and GALILEO) with. a A total of 358 patients were treated and evaluable for efficacy (217 with Eylea) in the two studies COPERNICUS and GALILEO. Patient ages ranged from 22 to 89 years with a mean of 64 years. In the CRVO studies, approximately 52% (112/217) of the patients randomised to treatment with Eylea were 65 years of age or older, and approximately 18% (38/217) were 75 years of age or older. In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg Eylea administered every 4 weeks (2Q4), or the control group receiving sham injections every 4 weeks for a total of 6 injections. -deleted -inserted.

In Figure 2:

In GALILEO, 86.4% (n=89) of the Eylea group and 79.4% (n=54) of the sham group had perfused CRVO at baseline. At week 24, this was 91.8% (n=89) in the Eylea group and 85.5% (n=47) in the sham group. These proportions were maintained at week 76, with 84.3% (n=75) in the Eylea group and 84.0% (n=42) in the sham group. The proportion of perfused patients in the Eylea group was high in the GALILEO study at baseline 86.4%; (n = 89). Perfusion at week 24 primary endpoint was 91.8% (n = 89). The patients were largely able to maintain their perfusion status until week 76, 84.3% (n =
75). The number of perfused patients that started on sham was 79.4% (n = 54) at baseline. Perfusion at week 24 primary endpoint was 85.5% (n = 47). Patients in the sham group were switched to Eylea according to pre-specified criteria at week 52, 83.7% (n = 41) were perfused at this time. The patients were able to maintain their perfusion status until week 76, 84.0% (n = 42).

In COPERNICUS, 67.5% (n = 77) of the Eylea group and 68.5% (n = 50) of the sham group had perfused CRVO at baseline. At week 24, this was 87.4% (n = 90) in the Eylea group and 58.6% (n = 34) in the sham group. These proportions were maintained at week 100 with 76.8 % (n = 76) in the Eylea group and 78% (n = 39) in the sham group. Patients in the sham group were eligible to receive Eylea from week 24.
The proportion of perfused patients in the Eylea group in the COPERNICUS study at baseline was 67.5% (n = 77). Perfusion at week 24 primary endpoint was 87.4% (n = 90). After week 24, patients in the Eylea group were treated according to pre-specified criteria. At week 100, 76.8 % (n = 76) of patients were perfused. The percentage of perfused patients that started on sham was 68.5% (n = 50) at baseline. Perfusion at week 24 primary endpoint was 58.6% (n = 34). Patients in the sham arm were eligible to receive Eylea from week 24. The proportion of perfused patients increased to 83.9% (n = 47) at week 52 and was largely maintained until week 100, 78% (n = 39).
-deleted -inserted.

The beneficial effect of Eylea treatment on visual function was similar in the baseline subgroups of perfused and non-perfused patients. Treatment effects in other evaluable subgroups (e.g. age, gender, race, baseline visual acuity, CRVO duration) in each study were in general consistent with the results in the overall populations.

In combined data analysis of the GALILEO and COPERNICUS studies, Eylea demonstrated clinically meaningful changes from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA).

Treatment effects in all evaluable subgroups (e.g. age, gender, race, baseline visual acuity, retinal perfusion status, CRVO duration) in each study were in general consistent with the results in the overall populations.

Elderly population

In the CRVO studies, approximately 52% (112/217) of the patients randomised to treatment with Eylea were 65 years of age or older, and approximately 18% (38/217) were 75 years of age or older.-
deleted.

In: Macular oedema secondary to BRVO

The safety and efficacy of Eylea were assessed in a randomised, multi-centre, double-masked, active-controlled study in patients with macular oedema secondary to BRVO (VIBRANT) which included Hemi-Retinal Vein Occlusion. A total of 181 patients were treated and evaluable for efficacy (91 with Eylea) in the VIBRANT study.Patient ages ranged from 42 to 94 years with a mean of 65 years. In the BRVO study, approximately 58% (53/91) of the patients randomised to treatment with Eylea were 65 years of age or older, and approximately 23% (21/91) were 75 years of age or older. In the study, patients were randomly assigned in a 1:1 ratio to either 2 mg Eylea administered every 8 weeks following 6 initial monthly injections’ or laser photocoagulation administered at baseline (laser control group). Patients in the laser control group could receive additional laser photocoagulation (called ‘rescue laser treatment’) beginning at week 12, if needed. The with a minimum interval between laser photocoagulation treatments was of 12 weeks. Based on pre-specified criteria, Beginning at week 24, patients in the laser treatment group could receive rescue treatment with Eylea 2mg from week 24, if needed, administered every 4 weeks for 3 months followed by intravitreal injections every 8 weeks,. based on pre-specified criteria. Patient ages ranged from 42 to 94 years with a mean of 65 years.

In the VIBRANT study, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline . At week 24, and the Eylea group was superior to laser control. for the primary endpoint
.

Change in visual acuity at week 24 compared to baseline was Aa secondary efficacy variable endpoint was change in visual acuity at week 24 compared to baseline, which was statistically significant in favour of Eylea in the VIBRANT study. The difference between treatment groups was statistically significant in favour of Eylea. The course of visual improvement was rapid and peaked maximal improvement was achieved at 3 months 3 with subsequent stabilisation maintenance of the effect on visual acuity and central retinal thickness until month 6 and subsequent maintenance of the effect until month 12.

In the laser group 67 patients received rescue treatment with Eylea beginning at week 24 (Active Control/ Eylea 2mg group) which resulted in improvement of. In this treatment group visual acuity improved by about 5 letters from week 24 to 52.

In: Figure 3

Elderly population
In the BRVO study, approximately 58% (53/91) of the patients randomised to treatment with Eylea were 65 years of age or older, and approximately 23% (21/91) were 75 years of age or older.

Diabetic macular oedema

The safety and efficacy of Eylea were assessed in two randomised, multi-centre, double-masked, active-controlled studies in patients with DME (VIVIDDME and VISTADME). A total of 862 patients randomised and were treated patients were and evaluable for efficacy. Of those, 576 were randomised to the with Eylea. Patient ages ranged from 23 to 87 years with a mean of 63 years. In the DME studies, approximately 47% (268/576) of the patients randomised to treatment with Eylea were 65 years of age or older, and approximately 9% (52/576) were 75 years of age or older. The majority of patients in both studies had Type II diabetes. groups in two studies (VIVIDDME and VISTADME).

Patient ages ranged from 23 to 87 years with a mean of 63 years.
The majority of patients in both studies had Type II diabetes.

In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at Week 52 as measured by ETDRS letter score. and both Both Eylea 2Q8 and Eylea 2Q4 groups demonstrated were shown to have efficacy that was statistically significantlyce and were superior to the control group. This benefit was maintained through week 100. -deleted -inserted.

In: Figure 4

An independent comparative trial (DRCR.net Protocol T) utilised a dosing regimen based on strict OCT and vision re-treatment criteria. In the aflibercept treatment group (n = 224) at week 52, this treatment regimen resulted in patients receiving a mean of 9.2 injections, which is similar to the administered number of doses in the Eylea 2Q8 group in VIVIDDME and VISTADME, while overall efficacy of the aflibercept treatment group in Protocol T was comparable to the Eylea 2Q8 group in VIVIDDME and VISTADME. A 13.3 mean letter gain with 42% of patients gaining at least 15 letters in vision from baseline was observed in Protocol T. Ocular and systemic safety profiles (including ATEs) were similar to VIVIDDME and VISTADME -was inserted.

Elderly population
In the DME phase III studies, approximately 47% (268/576) of the patients randomised to treatment with Eylea were 65 years of age or older, and approximately 9% (52/576) were 75 years of age or older. Efficacy and safety outcomes were consistent with the outcomes of the overall population
.-was deleted.

Myopic choroidal neovascularisation

The safety and efficacy of Eylea were assessed in a randomised, multi-centre, double-masked, sham-controlled study in treatment-naïve, Asian patients with myopic CNV.A total of 121 patients were treated and evaluable for efficacy (90 with Eylea). Patient ages ranged from 27 to 83 years with a mean of 58 years. In the myopic CNV study, approximately 36% (33/91) of the patients randomised to treatment with Eylea were 65 years of age or older, and approximately 10% (9/91) were 75 years of age or older. -was removed.

A total of 121 patients were treated and evaluable for efficacy (90 with Eylea). Their age ranged from 27 to 83 years with a mean of 58 years.- was deleted.


In:
Figure 5


Elderly population
In the myopic CNV study, approximately 36% (33/91) of the patients randomised to treatment with Eylea were 65 years of age or older, and approximately 10% (9/91) were 75 years of age or older.-was deleted.


10. DATE OF REVISION OF THE TEXT
11/2015 -was deleted
06/2016 -was inserted

 

 

 

 

 

Updated on 8 January 2016 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 7 January 2016 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
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4.8       Undesirable effects

 

Summary of the safety profile

 

A total of 2,957 3,102 patients constituted the safety population in the eight phase III studies. Among those, 2,356 2,501 patients were treated with the recommended dose of 2 mg.

 

Serious ocular adverse reactions in the study eye related to the injection procedure have occurred in less than 1 in 2,200 1,900 intravitreal injections with Eylea and included blindness, endophthalmitis, retinal detachment, cataract traumatic, cataract, vitreous haemorrhage, cataract, vitreous detachment, and intraocular pressure increased (see section 4.4).

 

The most frequently observed adverse reactions (in at least 5% of patients treated with Eylea) were conjunctival haemorrhage (2425%), visual acuity reduced (1011%), eye pain (10%), cataract (68%), intraocular pressure increased (78%), vitreous detachment (7%), and vitreous floaters (67%). and cataract (6%).

 

Tabulated list of adverse reactions

 

The safety data described below include all adverse reactions from the eight phase III studies in the indications wet AMD, CRVO, BRVO, DME and myopic CNV with a reasonable possibility of causality to the injection procedure or medicinal product.

 

The adverse reactions are listed by system organ class and frequency using the following convention:

 

Very common (≥1/10), common (≥1/100 to <1/10),  uncommon (≥1/1,000 to <1/100), rare (³ 1/10,000 to < 1/1,000)

Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness.


 

Table 1:           All treatment-emergent adverse drug reactions reported in patients in phase III studies (pooled data of the phase III studies for the indications wet AMD, CRVO, BRVO, DME and myopic CNV)

System Organ Class

Very common

Common

Uncommon

Rare

Immune system disorders

 

 

Hypersensitivity***

 

Eye disorders

Visual acuity reduced,

Conjunctival haemorrhage,

Eye pain

Retinal pigment epithelial tear*,

Detachment of the retinal pigment epithelium,

Retinal degeneration,

Vitreous haemorrhage,

Cataract,

Cataract cortical

Cataract nuclear,

Cataract subcapsular,

Corneal erosion,

Corneal abrasion,

Intraocular pressure increased,

Vision blurred,

Vitreous floaters,

Vitreous detachment,Injection site pain,

Foreign body sensation in eyes,

Lacrimation increased,

Eyelid oedema,

Injection site haemorrhage,

Punctate keratitis,

Conjunctival hyperaemia,

Ocular hyperaemia

Endophthalmitis**,

Retinal detachment,

Retinal tear,

Iritis,

Uveitis,

Iridocyclitis,

Cataract cortical

Lenticular opacities,

Corneal oedema,

Corneal epithelium defect,

Injection site irritation,

Abnormal sensation in eye,

Eyelid irritation,

Anterior chamber flare,

Corneal oedema,

 

Blindness,

Uveitis

Cataract traumatic, Vitritis,

Hypopyon

 

* Conditions known to be associated with wet AMD. Observed in the wet AMD studies only.

**    Culture positive and culture negative endophthalmitis

***  including allergic reactions

 

Description of selected adverse reactions

 

 

The incidence of ATEs in the phase III wet AMD studies during the 96 weeks study duration was 3.3% (60 out of 1,824) in the combined group of patients treated with Eylea compared to 3.2% (19 out of 595) in patients treated with ranibizumab (see section 5.1)., The corresponding numbers in the DME studies during the first 10052 weeks  were 6.43.3% (1937 out of 578) (Eylea) and 4.22.8% (812 out of 287) (control group) (see section 5.1).

 

 

5.1     Pharmacodynamic properties

 

 

Diabetic macular oedema

 

Diabetic macular oedema is characterised by increased vasopermeability and damage to the retinal capillaries which may result in loss of visual acuity.

In patients treated with Eylea, the majority of whom were classified as having Type II diabetes, rapid and robust response in morphology (central retinal thickness [CRT]) as assessed by OCT was seen soon after treatment initiation. The mean change in CRT from baseline to week 52 was statistically significant favouring Eylea.

 

In the VIVID-DME and the VISTA-DME studiesy there were the mean decreases in CRT at week 52 were (-192.4 and -183.1 microns for the 2Q8 Eylea groups and -66.2 and -73.3 microns at week 52 for the Eylea 2Q8 and for the laser control groups, respectively). Also at the 52 week time point, in the VISTA-DME study there were mean decreases in retinal thickness on OCT (-183.1 and -73.3 microns for the Eylea 2Q8 and laser group, respectively). At week 100 the decrease was maintained with -195.8 and -191.1 microns for the 2Q8 Eylea groups and -85.7 and -83.9 microns for the control groups, in the VIVID-DME and VISTA-DME studies, respectively.

 

A ≥ 2 step improvement in DRSS was assessed in a pre-specified manner in VIVID-DME and VISTA-DME. The DRSS score was gradable in 73.7% of the patients in VIVID-DME and 98.3% of the patients in VISTA-DME. At week 52, 27.7% and 29.1% of the Eylea 2Q8 groups, and 7.5% and 14.3% of the control groups experienced a ≥2 step improvement in the DRSS. At week 100, the respective percentages were 32.6% and 37.1% of the Eylea 2Q8 groups and 8.2% and 15.6% of  the control groups.

 

 

Macular oedema secondary to CRVO

 

The safety and efficacy of Eylea were assessed in two randomised, multi-centre, double-masked, sham-controlled studies in patients with macular oedema secondary to CRVO. A total of 358 patients were treated and evaluable for efficacy (217 with Eylea) in the two studies COPERNICUS and GALILEO. In both studies, patients were randomly assigned in a 3:2 ratio to either 2 mg Eylea administered every 4 weeks (2Q4) or the control group receiving sham injections every 4 weeks for a total of 6 injections.

 

After 6 monthly injections, patients received treatment only if they met pre-specified retreatment criteria, except for patients in the control group in the GALILEO study who continued to receive sham (control to control) until week 52. Starting from this timepoint all patients were offered treatment if they met pre-specified criteria.

 

Patient ages ranged from 22 to 89 years with a mean of 64 years.

 

In both studies, the primary efficacy endpoint was the proportion of patients who gained at least 15 letters in BCVA at week 24 compared to baseline.

 

Change in visual acuity at week 24 compared to baseline was a secondary efficacy variable in both COPERNICUS and GALILEO studies.

 

The difference between treatment groups was statistically significant in favour of Eylea in both studies. In both pivotal studies the maximal improvement in visual acuity has been achieved at month 3 with subsequent stabilisation of the effect on visual acuity and central retinal thickness until month 6. The statistically significant difference was maintained through week 52.

 

Detailed results from the analysis of both studies are shown in the Table 3 and Figure 2 below.

 


Table 3:           Efficacy outcomes at week 24, week 52 and week 76/100 (Full Analysis Set with LOCFC)) in COPERNICUS and GALILEO studies

 

Efficacy Outcomes

COPERNICUS

GALILEO

24 Weeks

52 Weeks

100 Weeks

24 Weeks

52 Weeks

76 Weeks

Eylea

2 mg Q4

(N = 114)

Control

 

(N= 73)

Eylea

2 mg

(N = 114)

 ControlE)

 (N =73)

Eylea F)

2 mg

(N= 114)

Control E,F)

(N=73)

Eylea

2 mg Q4

(N = 103)

Control

 

(N = 68)

Eylea

2 mg

(N = 103)

Control

(N = 68)

Eylea G)

2 mg

(N = 103)

Control G)

 

(N = 68)

Proportion of patients who gained at least 15 letters in BCVAC) from baseline

56%

12%

55%

30%

49.1%

23.3%

60%

22%

60%

32%

57.3%

29.4%

Weighted differenceA,B,E)

(95% CI)

44.8%
(33.0, 56.6)

 

25.9%
(11.8, 40.1)

 

26.7%
(13.1, 40.3)

 

38.3%
(24.4, 52.1)

 

27.9%
(13.0, 42.7)

 

28.0%
(13.3, 42.6)

 

p-value

p < 0.0001

 

p = 0.0006

 

p=0.0003

 

p < 0.0001

 

p = 0.0004

 

p=0.0004

 

Mean change in BCVA as measured by ETDRSC) letter score from baseline (SD)

17.3
(12.8)

‑4.0
(18.0)

16.2
(17.4)

3.8
(17.1)

13.0
(17.7)

1.5
(17.7)

18.0
(12.2)

3.3
(14.1)

16.9
(14.8)

3.8
(18.1)

13.7
(17.8)

6.2
(17.7)

Difference in LS meanA,C,D,E)
(95% CI)

21.7
(17.4, 26.0)

 

12.7
(7.7, 17.7)

 

11.8
(6.7, 17.0)

 

14.7
(10.8, 18.7)

 

13.2
(8.2, 18.2)

 

7.6
(2.1, 13.1)

 

p-value

p < 0.0001

 

p < 0.0001

 

p < 0.0001

 

p < 0.0001

 

p < 0.0001

 

p=0.0070

 


A)  Difference is Eylea 2 mg Q4 weeks minus control

B)  Difference and confidence interval (CI) are calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for region (America vs. rest of the world for COPERNICUS and Europe vs. Asia/Pacific for GALILEO) and baseline BCVA category (> 20/200 and ≤ 20/200)

C)  BCVA: Best Corrected Visual Acuity
ETDRS: Early Treatment Diabetic Retinopathy Study
LOCF: Last Observation Carried Forward
SD: Standard deviation
LS: Least square means derived from ANCOVA

D)  LS mean difference and confidence interval based on an ANCOVA model with factors treatment group, region (America vs. rest of the world for COPERNICUS and Europe vs. Asia/Pacific for GALILEO) and baseline BCVA category (> 20/200 and ≤ 20/200)

E)  In COPERNICUS study, control group patients could receive Eylea on an as-needed basis as frequently as every 4 weeks during week 24 to week 52; patients had visits every 4 weeks.

F)   In COPERNICUS study, both control group and Eylea 2mg patients received Eylea 2 mg on an as-needed basis as frequently as every 4 weeks starting from Week 52 to Week 96; patients had mandatory quarterly visits but may have been seen as frequently as every 4 weeks if necessary.

G)   In GALILEO study, both control group and Eylea 2mg patients received Eylea 2 mg on an as-needed basis every 8 weeks starting from Week 52 to Week 68; patients had mandatory visits every 8 weeks.


 

Figure 2:          Mean change from Baseline to Week 76/100 in Visual Acuity by Treatment Group for the COPERNICUS and GALILEO Studies (Full Analysis Set)

The proportion of perfused patients in the Eylea group was high in the GALILEO study at baseline 86.4%; (n = 89). Perfusion at week 24 primary endpoint was 91.8% (n = 89). The patients were largely able to maintain their perfusion status until week 76, 84.3%; (n = 75).  The number of perfused patients that started on sham was 79.4% (n = 54) at baseline. Perfusion at week 24 primary endpoint was 85.5% (n = 47). Patients in the sham group were switched to Eylea according to pre-specified criteria at week 52, 83.7% (n = 41) were perfused at this time. The patients were able to maintain their perfusion status until week 76, 84.0% (n = 42). 

 

The proportion of perfused patients in the Eylea group in the COPERNICUS study at baseline was 67.5% (n = 77). Perfusion at week 24 primary endpoint was 87.4%; (n = 90). After week 24, patients in the Eylea group were treated according to pre-specified criteria. At week 100, 76.8 % (n = 76) of patients were perfused. The percentage of perfused patients that started on sham was 68.5% (n = 50) at baseline.  Perfusion at week 24 primary endpoint was 58.6% (n = 34). Patients in the sham arm were eligible to receive Eylea from week 24. The proportion of perfused patients increased to 83.9% (n = 47) at week 52 and was largely maintained until week 100, 78%; (n = 39).

 

The beneficial effect of Eylea treatment on visual function was similar in the baseline subgroups of perfused and non-perfused patients.

 

In combined data analysis of the GALILEO and COPERNICUS studies, Eylea demonstrated clinically meaningful changes from baseline in pre-specified secondary efficacy endpoint National Eye Institute Visual Function Questionnaire (NEI VFQ-25). The magnitude of these changes was similar to that seen in published studies, which corresponded to a 15-letter gain in Best Corrected Visual Acuity (BCVA).

 

Treatment effects in all evaluable subgroups (e.g. age, gender, race, baseline visual acuity, retinal perfusion status, CRVO duration) in each study were in general consistent with the results in the overall populations.

 

Elderly population

 

In the CRVO studies, approximately 52% (112/217) of the patients randomised to treatment with Eylea were 65 years of age or older, and approximately 18% (38/217) were 75 years of age or older.

 

 

Diabetic macular oedema

 

The safety and efficacy of Eylea were assessed in two randomised, multi-centre, double-masked, active-controlled studies in patients with DME. A total of 862 randomised and treated patients were evaluable for efficacy. Of those, 576 were randomised to the Eylea groups in two studies (VIVIDDME and VISTADME). In each study, patients were randomly assigned in a 1:1:1 ratio to 1 of 3 dosing regimens:
1) Eylea administered 2 mg every 8 weeks following 5 initial monthly injections (Eylea 2Q8);
2) Eylea administered 2 mg every 4 weeks (Eylea 2Q4); and
3) macular laser photocoagulation (active control).
Beginning at week 24, patients meeting a pre-specified threshold of vision loss were eligible to receive additional treatment: patients in the Eylea groups could receive laser and patients in the laser control group could receive Eylea.

Patient ages ranged from 23 to 87 years with a mean of 63 years.

The majority of patients in both studies had Type II diabetes.

In both studies, the primary efficacy endpoint was the mean change from baseline in BCVA at Week 52 as measured by ETDRS letter score. Both Eylea 2Q8 and Eylea 2Q4 groups were shown to have efficacy that was statistically significantly superior to the laser control group. This benefit was maintained through week 100.

 Detailed results from the analysis of the VIVIDDME and VISTADME studies are shown in Table 5 and Figure 4 below.


 

Table 5:           Efficacy oOutcomes at wWeek 52 and week 100 (Full Analysis Set with LOCF) in VIVIDDME and VISTADME sStudies

Efficacy Outcomes

VIVIDDME

VISTADME

52 Weeks

100 Weeks

52 Weeks

100 Weeks

Eylea

2 mg Q8 A

(N = 135)

Eylea

2 mg Q4

(N = 136)

Active Control

(laser)

(N = 132)

Eylea

2 mg Q8 A

(N = 135)

Eylea

2 mg Q4

(N = 136)

Active Control

(laser)

(N = 132)

Eylea

2 mg Q8 A

(N = 151)

Eylea

2 mg Q4

(N = 154)

Active Control

(laser)

(N = 154)

Eylea

2 mg Q8 A

(N = 151)

Eylea

2 mg Q4

(N = 154)

Active Control

(laser)

(N = 154)

Mean change in BCVA as measured by ETDRS E letter score from Baseline

10.7

10.5

1.2

9.4

11.4

0.7

10.7

12.5

0.2

11.1

11.5

0.9

     Difference in LS      
     mean B,C,E
     (97.5% CI)

9.1
(6.3, 11.8)

9.3
(6.5, 12.0)

 

8.2
(5.2, 11.3)

10.7
(7.6, 13.8)

 

10.45
(7.7, 13.2)

12.19
(9.4, 15.0)

 

10.1
(7.0, 13.3)

10.6
(7.1, 14.2)

 

Proportion of patients who gained at least 15 letters in BCVA E from Baseline

33%

32%

9%

 

31.1%

 

38.2%

 

12.1%

31%

42%

8%

 

33.1%

 

38.3%

 

13.0%

     Adjusted 
     Difference D,C,E
     (97.5% CI)

24%
(13.5, 34.9)

23%
(12.6, 33.9)

 

19.0%
(8.0, 29.9)

26.1%
(14.8, 37.5)

 

23%
(13.5, 33.1)

34%
(24.1, 44.4)

 

20.1%

(9.6, 30.6)

25.8%

(15.1, 36.6)

 

A  After treatment initiation with 5 monthly injections

 

 

B  LS mean and CI based on an ANCOVA model with baseline BCVA measurement as a covariate and a factor for treatment group. Additionally, region (Europe/Australia vs. Japan) had been included as factor for VIVIDDME, and history of MI and/or CVA as a factor for VISTADME.

C Difference is Eylea group minus active control (laser) group

D  Difference with confidence interval (CI) and statistical test  is calculated using Mantel-Haenszel weighting scheme adjusted by region (Europe/Australia vs. Japan) for VIVIDDME and medical history of MI or CVA for VISTADME

E  BCVA: Best Corrected Visual Acuity
ETDRS: Early Treatment Diabetic Retinopathy Study
LOCF: Last Observation Carried Forward
LS: Least square means derived from ANCOVA
CI: Confidence interval


 

Figure 4:          Mean change in BCVA as Measured by ETDRS Letter Score from Baseline to Week 52100 in VIVIDDME and VISTADME Studies

 

 

 

The VISTADME second year outcomes are in line with the results from the primary and secondary endpoints obtained at week 52.

Treatment effects in evaluable subgroups (e.g., age, gender, race, baseline HbA1c, baseline visual acuity, prior anti-VEGF therapy) in each study and in the combined analysis were generally consistent with the results in the overall populations.

 

In the VIVIDDME and VISTADME studies, 36 (9%) and 197 (43%) patients received prior anti-VEGF therapy, respectively, with a 3-month or longer washout period. Treatment effects in the subgroup of patients who had previously been treated with a VEGF inhibitor prior to study participation were similar to those seen in patients who were VEGF inhibitor naïve prior to study participation.

 

Patients with bilateral disease were eligible to receive anti-VEGF treatment in their fellow eye if determined to be necessary by the physician. In the VISTADME study, 198 217(6570.7%) of Eylea patients received bilateral Eylea injections until week 100; in the VIVIDDME study, 70 97(2635.8%) of Eylea patients received a different anti-VEGF treatment in their fellow eye.

 

 

Elderly population

 

In the DME phase III studies, approximately 47% (268/576) of the patients randomised to treatment with Eylea were 65 years of age or older, and approximately 9% (52/576) were 75 years of age or older. Efficacy and safety outcomes were consistent with the outcomes of the overall population.

 

 

5.2     Pharmacokinetic properties

 

 

Absorption / Distribution

 

In a pharmacokinetic sub-study in 6 neovascular wet AMD patients with frequent sampling, maximum plasma concentrations of free aflibercept (systemic Cmax) were low, with a mean of approximately 0.02 microgram/ml (range 0 to 0.054) within 1 to 3 days after a 2 mg intravitreal injection, and were undetectable two weeks following dosage in almost all patients. Aflibercept does not accumulate in the plasma when administered intravitreally every 4 weeks.

 

 

10.     DATE OF REVISION OF THE TEXT

 

110/2015

 

 

Updated on 21 December 2015 PIL

Reasons for updating

  • Change to side-effects
  • Change to date of revision

Updated on 9 November 2015 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company



In section 4.1 Therapeutic indications, the following bullet point has been added:

Visual impairment due to myopic choroidal neovascularisation (myopic CNV) (see section 5.1).

 

In section 4.2 Posology and method of administration, the following text has been added:

Myopic choroidal neovascularisation

The recommended dose for Eylea is a single intravitreal injection of 2 mg aflibercept equivalent to 50 microlitres.

Additional doses may be administered if visual and/or anatomic outcomes indicate that the disease persists. Recurrences should be treated as a new manifestation of the disease.

The schedule for monitoring should be determined by the treating physician.

The interval between two doses should not be shorter than one month.

In the same section, myopic CNV has been added:

There is no relevant use of Eylea in the paediatric population in the indications wet AMD, CRVO, BRVO, and DME and myopic CNV

 

In section 4.3 Contraindications, the following text has been altered to include:

There are limited data on safety in the treatment of patients with CRVO, BRVO, or DME or myopic CNV

As with other intravitreal anti-VEGF treatments for AMD, CRVO, BRVO, and DME and myopic CNV the following also applies:

In myopic CNV there is no experience with Eylea in the treatment of non-Asian patients, patients who have previously undergone treatment for myopic CNV, and patients with extrafoveal lesions.

 

In section 4.8 Undesirable effects, the following text has been added:

A total of 2,957 3,073 patients constituted the safety population in the seven eight phase III studies. Among those, 2,356 2,472 patients were treated with the recommended dose of 2 mg.

Serious adverse reactions related to the injection procedure have occurred in less than 1 in 2,200 intravitreal injections with Eylea and included blindness, endophthalmitis, retinal detachment, cataract traumatic, vitreous haemorrhage, cataract, vitreous detachment, and intraocular pressure increased (see section 4.4).

The most frequently observed adverse reactions (in at least 5% of patients treated with Eylea) were conjunctival haemorrhage (24.924%), visual acuity reduced (10.710%), eye pain (9.910%), intraocular pressure increased (7.17%), vitreous detachment (6.87%), vitreous floaters (6.66%) and cataract (6.66%).

Tabulated list of adverse reactions

The safety data described below include all adverse reactions from the seven eight phase III studies in the indications wet AMD, CRVO, BRVO, and DME and myopic CNV with a reasonable possibility of causality to the injection procedure or medicinal product.

 Table 1: All treatment-emergent adverse drug reactions reported in patients in phase III studies (pooled data of the phase III studies for the indications  wet AMD, CRVO, BRVO, and DME and myopic CNV)

 

 

 

System Organ Class

 

Very common

 

Common

 

Uncommon

 

Rare

Immune system disorders

 

 

Hypersensitivity***

 

Eye disorders

Visual acuity reduced, Conjunctival

haemorrhage,

Eye pain

Retinal pigment epithelial tear*, Detachment of the retinal pigment epithelium,

Retinal degeneration, Vitreous haemorrhage, Cataract,

Cataract nuclear, Cataract subcapsular, Cataract cortical, Corneal erosion, Corneal abrasion,

Intraocular pressure increased, Vision blurred,

Vitreous floaters,  Corneal oedema, Vitreous detachment, Injection site pain,  Eye pain

Foreign body sensation in eyes,

Lacrimation increased, Eyelid oedema,

Injection site haemorrhage, Punctate keratitis, Conjunctival hyperaemia, Ocular hyperaemia

Blindness, Endophthalmitis**, Retinal detachment,

Retinal tear, Iritis,

Uveitis, Iridocyclitis, Cataract cortical,

Lenticular opacities, Corneal oedema,

 

Corneal epithelium defect,

Injection site irritation,  Abnormal sensation

in eye,

Eyelid irritation, Anterior chamber flare

Blindness, Uveitis, Cataract

traumatic,

Vitritis, Hypopyon


 

* Conditions known to be associated with wet AMD. Observed in the wet AMD studies only.

**  Culture positive and culture negative endophthalmitis

*** including allergic reactions

 

The incidence of ATEs in the myopic CNV study during the 48 weeks study duration was 1.1% (1 out of 91) (Eylea) compared to 0% (0 out of 31) (control group).

 

In section 5.1 Pharmacodynamic properties, the following text has been added

Retinal thickness on OCT at week 24 compared to baseline was a secondary efficacy variable in the COPERNICUS and GALILEO studies (CRVO) and the VIBRANT study (BRVO). In all three studies, the mean change in CRT from baseline to week 24 was statistically significant, favouring Eylea.

In the COPERNICUS and GALILEO studies (CRVO) the mean decrease from baseline in CRTretinal thickness on OCT at week 24 was significantly greater in patients treated with Eylea 2 mg every month than in the control group (-457 microns vs. -145 microns in COPERNICUS, and -449 microns vs. -169 microns in GALILEO). The decrease from baseline in retinal thickness was maintained to the end of study, week 100 in COPERNICUS, and to week 76 in GALILEO.

In the VIBRANT study (BRVO) the mean decrease from baseline in CRTretinal thickness on OCT at week 24 was significantly greater in patients treated with Eylea 2 mg every month than in the control group (-280 microns vs. -128 microns). This decrease from baseline was maintained to end of study, week 100 in COPERNICUS, week 76 in GALILEO, and to week 52 in VIBRANT.

Diabetic macular oedema

Diabetic macular oedema is characterised by increased vasopermeability and damage to the retinal capillaries which may result in loss of visual acuity.

In patients treated with Eylea, rapid and robust response in morphology (central retinal thickness [CRT]) as assessed by OCT was seen soon after treatment initiation. The mean change in CRT from baseline to week 52 was statistically significant favouring Eylea.

In the VIVID-DME study there were mean decreases in CRT retinal thickness on optical coherence tomography (OCT) (of -192.4 and -66.2 microns at week 52 for the Eylea 2Q8 and laser group, respectively). Likewise,Also at the 52 week time point, in the VISTA-DME study there were mean decreases in CRTretinal thickness on OCT ( of -183.1 and -73.3 microns at week 52 for the Eylea 2Q8 and laser group, respectively).

Myopic choroidal neovascularisation

Myopic choroidal neovascularisation (myopic CNV) is a frequent cause of vision loss in adults with pathologic myopia. It develops as a wound healing mechanism consequent to Bruch’s membrane ruptures and represents the most vision-threatening event in pathologic myopia.

In patients treated with Eylea in the MYRROR study (one injection given at start of therapy, with additional injections given in case of disease persistence or recurrence), retinal thickness assessed by OCT decreased soon after treatment initiation and the mean CNV lesion size was reduced. The mean change in CRT from baseline to week 24 was statistically significant favouring Eylea (-79 microns and -4 microns for the Eylea 2 mg treatment group and the control group, respectively). The decrease from baseline in retinal thickness in the Eylea 2 mg group was maintained through week 48.

 

The following text has been added to the same section:

Myopic choroidal neovascularisation

The safety and efficacy of Eylea were assessed in a randomised, multi-centre, double-masked, sham-controlled study in treatment-naïve, Asian patients with myopic CNV. Patients were randomly assigned in a 3:1 ratio to receive either 2 mg Eylea intravitreally or sham injections administered once at study start with additional injections given monthly in case of disease persistence or recurrence until week 24, when the primary endpoint was assessed. At week 24, patients initially randomised to sham were eligible to receive the first dose of Eylea. Following this, patients in both groups continued to be eligible for additional injections in case of disease persistence or recurrence.

A total of 121 patients were treated and evaluable for efficacy (90 with Eylea). Their age ranged from 27 to 83 years with a mean of 58 years.

The difference between treatment groups was statistically significant in favour of Eylea for the primary endpoint (change in BCVA) and confirmatory secondary efficacy endpoint (proportion of patients who gained 15 letters in BCVA) at week 24 compared to baseline. Differences for both endpoints were maintained through week 48.

Detailed results from the analysis of the MYRROR study are shown in Table 6 and Figure 5 below.

 

Table 6:             Efficacy outcomes at week 24 (primary analysis) and week 48 in MYRROR study (Full Analysis Set with LOCFA))

Efficacy Outcomes

MYRROR

24 Weeks

48 Weeks

Eylea 2mg

(N = 90)

Sham

(N = 31)

Eylea 2mg

(N = 90)

Sham/
Eylea 2mg

(N = 31)

Mean change in BCVA letter score as measured by ETDRS from baseline (SD) B)

12.1

(8.3)

-2.0

(9.7)

13.5
(8.8)

3.9

(14.3)

         Difference in LS mean C,D, E)

        (95% CI)

14.1

(10.8, 17.4)

 

 

9.5

(5.4, 13.7)

 

 

Proportion of patients who gained at least 15 letters in BCVAB) from baseline

38.9%

9.7%

50.0%

29.0%

        Weighted difference D, F)

        (95% CI)

 

29.2%

(14.4, 44.0)

 

 

21.0%

(1.9, 40.1)

 

 

A)                LOCF: Last Observation Carried Forward

B)                BCVA: Best Corrected Visual Acuity

ETDRS: Early Treatment Diabetic Retinopathy Study

SD: Standard Deviation

C)                LS mean: Least square means derived from ANCOVA model

D)                CI: Confidence Interval

E)                LS mean difference and 95% CI based on an ANCOVA model with treatment group and country (country designations) as fixed effects, and baseline BCVA as covariant.

F)                 Difference and 95% CI are calculated using Cochran-Mantel-Haenszel (CMH) test adjusted for country (country designations)

 

Figure 5:         Mean Change from Baseline to Week 48 in Visual Acuity by Treatment Group for the MYRROR Study (Full Analysis Set, LOCF)