XTEND Non-interventional Study
Research type
Research Study
Full title
XTEND – evaluation of an eXtended and proactive dosing regimEn in treatment-Naïve patients with wet age related macular Degeneration (wAMD)
IRAS ID
260130
Contact name
Clare Bailey
Contact email
Sponsor organisation
Bayer
Duration of Study in the UK
4 years, 3 months, 1 days
Research summary
Research Summary
Age-related macular degeneration (AMD) is the leading cause of blindness in people over the age of 50 in developed countries and is characterised by central vision loss.
Wet AMD (wAMD), the most serious and severe form of AMD and occurs when blood vessels grow abnormally beneath the macula. This process is called angiogenesis and is driven by the presence of Vascular Endothelial Growth Factor (VEGF).
These abnormal vessels leak fluid and blood eventually leading to irreversible vision loss if left untreated.
This prospective, non-interventional, multicentre study will collect data on patients diagnosed with wAMD who are treated with aflibercept, a therapeutic antibody that binds to VEGF, to examine the effectiveness of proactive treatment regimens, in a routine clinical setting.
The aim of the study is to examine the effectiveness of proactive treatment regimens of Intravitreal (IVT) aflibercept following the broadening of the label in 2018 to allow flexible treatments after the loading phase, in a routine clinical setting in treatment-naïve patients diagnosed with wAMD.
The primary objective of this study is to describe the effectiveness of flexible proactive treatment approaches with intravitreal aflibercept (by evaluating the mean change in best corrected visual acuity [BCVA]) in treatment-naïve wAMD patients.
Additional secondary objectives will assess the effectiveness of flexible proactive treatment approaches by evaluating further visual and structural changes in the treated eye, usage and treatment patterns / approaches.
Summary of Results
Of the 1561 enrolled patients, 1548 patients were evaluated for safety and 1483 were included in the FAS. At baseline, the mean (±SD) VA in the study eye was 54.3 (±20.3) ETDRS letters for patients in the FAS (55.1 (±19.8) letters in patients from EU-type label countries (n=1170) and 51.5 (±21.7) letters in patients from non-EU-type label countries (n=313)). The median duration of IVT aflibercept treatment was 31.0 months with a mean number of applied IVT aflibercept injections in the study eye of 7.7 (±2.7) within 12 months, 11.3 (±5.3) within 24 months and 13.7 (±7.5) within 36 months from baseline. The mean time between IVT aflibercept injections in the study eye was 50.5 (±16.3) days within the first 12 months, 58.0 (±22.8) days within the first 24 months and 61.9 (±28.5) days within the first 36 months from baseline. The median duration between injections after 90 days from baseline increased after the country-specific start date of COVID-19 (8.0 (range: 3.7 - 20.0) weeks prior to and 9.9 (range: 3.7 - 130.1) weeks after the country-specific COVID-19 start date). The mean change in VA from baseline at 12 months which was the primary endpoint of the study was 4.6 (95 % CI 3.7, 5.4) ETDRS letters based on LOCF (4.8 (95 % CI 3.8, 5.8) letters in patients from EU-type label and 3.7 (95 % CI 1.9, 5.5) letters in patients from non-EU-type label countries). Similar results were found for analysis of FAS (OC) and FAS (Completers). A sensitivity analysis using ANCOVA revealed that the baseline VA letter score affected the change in VA at 12 months in such a way that the VA gain was 3 letters less for every 10 letters more at baseline. A substantial proportion of patients with a b months (36.6 % of the 415 patients with a baseline VA of % with a change between +4 and -4 letters and 25.8 % having lost 5 or more letters). The mean change in VA from baseline at 24 months was 2.3 (95 % CI 1.3, 3.3) ETDRS letters for the FAS (LOCF) (2.3 (95 % CI 1.2, 3.5) letters for patients from EU-type label and 2.3 (95 % CI 0.2, 4.4) for patients from non-EU type label countries). The mean change in VA letter score from baseline at 36 months was 0.9 (95 % CI -0.2, 1.9) ETDRS letters for the FAS (LOCF) (0.8 (95 % CI -0.5, 2.0) letters for patients from EU-type label and 1.2 (95 % CI -1.0, 3.4) for patients from non-EU-type label countries). Using LOCF, 25.7 % of patients had a change in VA of -4 to +4 letters compared to baseline at 12 months. A gain of 5 or more letters compared to baseline was found in 51.2% of patients with 23.3 % having gained even 15 or more letters from baseline to 12 months. Besides, 21.8 % of patients were found to have lost 5 or more letters at 12 months, and 9.6 % had lost 15 or more letters. Patients with an intended T&E treatment schedule showed a numerically higher mean change in VA from baseline than patients for whom fixed dosing was intended (4.7 (±17.5) vs. 3.4 (±16.6) letters at 12 months; 2.8 (±19.4) vs. -0.6 (±20.3) letters at 24 months; 1.3 (±21.1) vs. -2.3 (±22.5) letters at 36 months). It should be noted that the treatment schedule intended at baseline was often not followed due to the COVID-19 pandemic. Starting with a baseline mean CRT in the study eye of 374.5 (±125.4) µm (377.3 (±130.0) µm in patients from EU-type label and 365.5 (±109.5) µm in patients from non-EU-type label countries), the mean change in CRT from baseline for the FAS (LOCF) was -106 (95 % CI -113.9, -98.8) µm at 12 months, -109 (95 % CI -116.8, -101.8) µm at 24 months and -110 (95 % CI -118.0, -102.7) µm at 36 months (EU type label countries: -107 (95 % CI -115.9, -98.1) µm at 12 months, -109 (95 % CI -118.3, -100.4) µm at 24 months, -110 (95 % CI -119.1, -100.8) µm at 36 months; non-EU type label countries: -104 (95 % CI -118.6, -90.0) µm at 12 months, -109 (95 % CI -122.3, -96.1) µm at 24 months and -112 (95 % CI -124.9, -98.2) µm at 36 months). In a sensitivity analysis including only patients with baseline data assessed prior to the COVID-19 pandemic and imputing all their follow-up VA values which were assessed after the country-specific start date of COVID-19 impact by LOCF, the mean change in VA from baseline was 5.2 (95 % CI 4.3, 6.1) letters after 12 months, 24 months and 36 months. When applying the same imputation methods for calculation of CRT outcomes, the mean change in CRT from baseline was -104.4 (95 % CI -112.8, -96.0) µm at 12 months, -108.1 (95 % CI -116.4, -99.8) µm at 24 months and -108.6 (95 % CI -117.1, -100.1) µm at 36 months. For another sensitivity analysis regarding functional outcomes, all patients who received their regular end of observation before the country-specific start date of COVID-19 or who received their first IVT aflibercept injection 180 days prior to the country-specific start date of (n=1211). In the LOCF analysis, the mean change of VA was 4.4 (95 % CI 2.6, 6.1) letters at 12 months, 1.0 (95 % CI -1.0, 3.0) letters at 24 months and -0.5 (95 % CI -2.8, 1.7) at 36 months The mean change of VA compared to (95 % CI 3.6, 5.6) letters at 12 months, 2.6 (95 % CI 1.5, 3.8) letters at 24 months and 1.2 (95 % CI -0.1, 2.4) letters at 36 months. The mean change in CRT from baseline was (-97.2 (95 % CI -117.5, -76.9) µm vs. -107.5 (95 % CI -115.6, -99.3) µm) and similar between both groups at later timepoints (-106.2 (95 % CI -123.9, -88.4) µm vs. -109.5 (95 % CI -117.8, -101.2) µm at 24 months and -110.3 (95 % CI -128.2, -92.5) µm vs. -108.8 (95 % CI -117.2, -100.4) µm at 36 months). At baseline, 1.8 % of the FAS (OC) patients did not have any fluid in the study eye. Sub-retinal, intra-retinal, and sub-retinal pigment epithelium (RPE) fluid was present in the study eye in 68.5 %, 50.4 %, and 30.8 % of patients, respectively. At 12 months, the percentage of patients without any fluid had increased to 37.5 % of patients with 17.4 %, 12.7 %, and 6.7 % of patients having sub-retinal, intra-retinal, and sub-RPE fluid, respectively. At 24 months, absence of fluid was documented in 32.2 % of patients. However, the percentages of patients with documented presence of sub-retinal (14.2 %), intra-retinal (9.7 %), and sub-RPE fluid (5.3 %) were nominally lower than at the 12 months visit. At 36 months, absence of any fluid was documented for only 27.6 % of patients, but the percentages of patients with sub-retinal, intra-retinal and sub-RPE fluid present in the study eye were again lower than before (11.1 %, 8.1 % and 3.7 %, respectively). At baseline, 59.2 % of patients had documented pigment epithelial detachment (PED). The percentage decreased to 30.8 % at 12 months, 23.9 % at 24 months and 20.5 % at 36 months. Due to the high number of patients with missing data regarding presence/absence of fluid especially at later time points, these results should be interpreted with caution. Most frequently, with a mean number of 4.7 (±3.0) visits within 12 months, 7.5 (±5.1) visits within 24 months and 9.5 (±6.9) visits within 36 months from baseline, combined visits for injection and patient monitoring were performed. A mean number of 6.7 (±2.8) VA tests per patient was performed within 12 months, of 10.0 (±4.8) VA tests within 24 months and of 12.6 (±6.7) VA tests within 36 months from baseline. Mean numbers of 6.1 (±2.7), 9.6 (±4.8) and 12.3 (±6.7) OCT assessments were performed within 12, 24 and 36 months from baseline, respectively. The most frequently detected abnormal findings during fundoscopy were choroidal neovascularization (CNV) in 47.5% of all FAS patients, drusen (42.4 %), PED (40.8 %), RPE abnormalities (38.3 %), retinal hemorrhage (29.5 %), atrophy (26.4 %) and edema (24.9 %). TEAEs were documented in 724 (46.8 %) of the 1548 patients in the SAF, of which 300 (19.4 %) patients had non-ocular TEAEs and 568 (36.7 %) patients had ocular TEAEs. For 426 (27.5 %) patients in the SAF, at least one ocular TEAE had occurred in the study eye. Among them, the most frequently ocular TEAEs were cataract (6.5 % of the SAF), retinal haemorrhage (3.4 %), and blepharitis (2.1 %). In 25 (1.6 %) patients, serious drug-related TEAEs had occurred, including 6 (0.4%) patients with serious drug related non-ocular TEAEs and 19 (1.2 %) patients with serious drug-related ocular TEAEs. The percentage of patients with documented TEAEs was nominally lower in non-EU-type label countries than in EU-type label countries, especially regarding ocular TEAEs (24.3 % vs. 40.0 %)
REC name
South Central - Oxford C Research Ethics Committee
REC reference
19/SC/0148
Date of REC Opinion
20 Mar 2019
REC opinion
Favourable Opinion