Tulosta

Afliberseptin teho kostean silmänpohjan ikärappeuman hoidossa

Näytönastekatsaukset
30.3.2016
Raija Sipilä

Näytön aste: B

Lasiaiseen kuukausittain tai harvemmin annosteltava aflibersepti (0,5–2 mg) on ilmeisesti yhtä tehokas kostean silmänpohjan ikärappeuman hoidossa ylläpitämään näköntarkkuutta kuin kuukausittain annosteltava ranibitsumabi (0,5 mg).

Two phase-3 studies (VIEW 1, VIEW 2) «Heier JS, Brown DM, Chong V ym. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119:2537-48 »1 compared monthly and every-2-month dosing of intravitreal aflibercept injection with monthly ranibizumab for patients with neovascular age-related macular degeneration (AMD).

The studies were double-masked (unmasked investigator performed the study drug or sham injection), multicenter, parallel-group, active-controlled and randomized.

Inclusion criteria were age >50 years with active subfoveal choroidal neovascularization (CNV) lesions (any subtype) secondary to AMD, juxtafoveal lesions with leakage affecting the fovea also were allowed; CNV comprising at least 50%of total lesion size; best corrected visual acuity (BCVA) between 73 and 25 Early Treatment Diabetic Retinopathy Study chart (ETDRS) letters (20/40 –20/320 Snellen equivalent). Patients with prior treatment for AMD in the study eye; total lesion size > 12 disc area; presence of other causes of CNV or ocular disease; presence of contraindications to ranibizumab were excluded.

VIEW 1 was conducted in USA and Canada and VIEW 2 in Europe, the Middle East, Asia and Latin America. A total of 2419 patients (VIEW 1 n=1217 and VIEW 2 n=1240) were randomized to intravitreal aflibercept 0.5 mg monthly (0.5q4, n=304/311), 2 mg monthly (2q4, n=304/313), 2 mg every 2 months after 3 initial monthly doses (2q8, n=303/313) (to maintain masking, sham injections were given at the interim 4-week visits after week 8), or ranibizumab 0.5 mg monthly (Rq4, n=306/303). The patients in VIEW 2 study had lightly more severe AMD at baseline and worse general health.

The primary end point was noninferiority (margin of 10%) of the aflibercept regimens to ranibizumab in the proportion of patients maintaining vision at week 52 (losing <15 letters on ETDRS chart). Secondary end points included mean change in BCVA, gaining >15 letters, change in Visual Function Questionnaire score, change in CNV area on fluorescein angiography, retinal thickness and persistent fluid. The margin for clinical equivalence was 5%. Endpoint assessment was performed every 4 weeks. Both full analysis and per protocol analysis were conducted. The drop-out rate for aflibercept groups were 7.1% (VIEW1) and 10.7% (VIEW2). The respective figures for ranibizumab groups were 7.2% and 8.9%.

Proportion of patients maintaining vision at week 52 for the 2q4, 0.5q4, and 2q8 regimens were 95.1%, 95.9%, and 95.1% for VIEW 1, and 95.6%, 96.3%, and 95.6% for VIEW 2. For monthly ranibizumab the proportion was 94.4%in both studies. Mean change in BCVA was +8.7 letters for Rq4 group, +9.3 for 2q4 group, and +8.4 for 2q8 group. In VIEW1 study 2q4 group was statistically significantly superior to other groups, gaining 10.9 letters. In integrated analysis of the two studies all aflibercept regimens produced similar improvements in anatomic measures.

  • Tutkimuksen laatu: tasokas
  • Sovellettavuus suomalaiseen väestöön: kohtalainen

Kommentti: VIEW1-tutkimuksen populaatiosta yli 95%oli valkoihoisia, VIEW2-tutkimus suoritettiin osin Euroopassa, mukana oli noin 20%aasialaisia. Tutkimusta sponsoroivat Regeneron Pharmaceuticals ja Bayer HealthCare. Sponsorit osallistuivat tutkimuksen suunnitteluun, tulosten analysointiin ja käsikirjoituksen laatimiseen.

The aim was to report disease-specific quality of life (QoL) data from VIEW 1 and VIEW 2 studies «Yuzawa M, Fujita K, Wittrup-Jensen KU ym. Improvement in vision-related function with intravitreal aflibercept: data from phase 3 studies in wet age-related macular degeneration. Ophthalmology 2015;12»2. The methods are described in more detail in the above abstract «Heier JS, Brown DM, Chong V ym. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119:2537-48 »1.

This analysis included patients who received intravitreal aflibercept 2.0 mg every 8 weeks after 3 initial monthly doses (2q8; n=607) or ranibizumab 0.5 mg every 4 weeks (Rq4; n=595).

The 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) was a secondary outcome for the studies. It was administered at baseline and at weeks 12, 24, 36, and 52. The assessments were conducted by masked trained interviewers by telephone in VIEW 1 and face-to-face in VIEW 2. Mean change from baseline to week 52 in composite score and in subscale scores were compared between the groups. Clinically meaningful change in subscore was defined as 4- to 6-point change. Full analysis was used: included were subjects who received study medication and had at least one postbaseline assessment. Last observation was carried forward.

Mean baseline NEI VFQ-25 composite scores were 69.6 for 2q8 group and 71.8 for Rq4 group in VIEW 1, and 71.3 and 72.9 for VIEW 2, respectively. Mean change from baseline to 52 weeks in composite score (pooled data ) showed meaningful improvement only in patients who gained 5 ETDRS letters or more (7.3 and 7.8 points for 2q8 and Rq4). Mean change from baseline to 52 weeks was similar for ranibizumab and aflibercept across all 12 subscales, with the greatest improvements noted for mental health and general vision (9.0-11.6 points, both treatments, both studies). Statistically significant difference between the groups were in 3 subscores (not defined) in VIEW 1 study and none in VIEW 2. Improvement of 4 points or more (both treatments, both studies) also was observed for subscales near vision, distance vision, role difficulties, and dependency. The improvements were attained by 6 months.

  • Tutkimuksen laatu: tasokas
  • Sovellettavuus suomalaiseen väestöön: kohtalainen

Kommentti: VIEW1-tutkimuksen populaatiosta yli 95%oli valkoihoisia, VIEW2-tutkimus suoritettiin osin Euroopassa, mukana oli noin 20%aasialaisia. Tutkimusta sponsoroivat Regeneron Pharmaceuticals ja Bayer HealthCare. Sponsorit osallistuivat tutkimuksen suunnitteluun, tulosten analysointiin ja käsikirjoituksen laatimiseen.

The purpose of the study was to determine efficacy and safety of intravitreal aflibercept in patients with AMD during a second year of variable dosing after a first-year fixed-dosing period «Schmidt-Erfurth U, Kaiser PK, Korobelnik JF ym. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology 2014;121»3.

The study is follow-up for VIEW 1 and VIEW 2 studies «Heier JS, Brown DM, Chong V ym. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119:2537-48 »1, therefore methods are described in more detail above.

Two randomized, double-masked, active-controlled, phase 3 trials. At baseline 2457 patients were randomised to receive 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4), 2 mg aflibercept every 4 weeks (2q4), 0.5 mg aflibercept every 4 weeks (0.5q4), or 2 mg aflibercept every 8 weeks (2q8) after 3 monthly injections. A total of 2235 patients entered the follow-up study and 2063 (91.0%) completed it. During weeks 52 through 96, patients received their original dosing assignment using an as-needed regimen with defined retreatment criteria and mandatory dosing at least every 12 weeks. Retreatment criteria were new persistent fluid on optical coherent tomography (OCT), increase in central retinal thickness of 100 um or more, loss of 5 or more ETDRS letters in conjuction with persistent fluid on OCT, new-onset classic neovascularization, new or persistent leak on fluorescein angiography, and new macular hemorrhage.

Main outcome measures were proportion of eyes at week 96 that maintained BCVA (lost <15 letters from baseline) and change from baseline in BCVA. Secondary outcomes were mean change in central retinal thickness and number of study injections.

Proportions of eyes maintaining BCVA across treatments were 94.4% to 96.1% at week 52 and 91.5% to 92.4% at week 96 (difference of aflibercept groups compared to ranibitsumab group -0.1 - +0.8%). Mean BCVA gains were 8.3 to 9.3 letters at week 52. At week 96 gain were 7.9, 7.6, 6.6, and 7.6 letters for Rq4, 2q4, 0.5q4, and 2q8 groups representing 1 to 2 letter loss compared to week 52. Proportion of patients who gained 15 letters or more was 31.6%, 31.2%, 28.1%, and 33.4% for Rq4, 2q4, 0.5q4 and 2q8 groups. Proportions of eyes without retinal fluid decreased from week 52 (60.3% to 72.4%) to week 96 (44.6% to 54.4%), and more 2q4 eyes were without fluid at weeks 52 and 96 than Rq4 eyes (difference of 10.4%, 95%confidence interval (CI) 4.9-15.9] and 9.0% [95%CI, 3.0-15.1]). Patients received on average 16.5, 16.0, 16.2, and 11.2 injections during the 96 weeks period and 4.7, 4.1, 4.6, and 4.2 injections during weeks 52 through 96 in the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively.

  • Tutkimuksen laatu: tasokas
  • Sovellettavuus suomalaiseen väestöön: kohtalainen

Kommentti: VIEW1-tutkimuksen populaatiosta yli 95% oli valkoihoisia, VIEW2-tutkimus suoritettiin osin Euroopassa, mukana oli noin 20%aasialaisia. Tutkimusta sponsoroivat Regeneron Pharmaceuticals ja Bayer HealthCare. Sponsorit osallistuivat tutkimuksen suunnitteluun, tulosten analysointiin ja käsikirjoituksen laatimiseen.

Meta-analysis and network meta-analysis «Schmid MK, Bachmann LM, Fäs L ym. Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis. Br J Ophthalmol 2015;99:141-6 »4 aimed at quantifying the gain in visual acuity and serious side effects of ranibizumab, bevacizumab and aflibercept in AMD.

Included were randomised controlled trials comparing aflibercept, bevacizumab or ranibizumab against placebo or in a head-to head fashion with at least one year follow-up data. Outcome measures had to include visual acuity and serious side effects.

Literature was searched until June 2013 from (Pre)Medline, EMBASE, SCOPUS, Cochrane Library (until April 2013), Science Citation Index and reference lists were searched. Separate searches for efficacy and side effects were performed. Outcomes were 1-year follow-up data of visual acuity (letters gained) and serious (vascular death, any death, stroke, myocardial infarction, transient ischaemic attack) and thrombotic events.

Meta-analysis included 11 trials (8341 patients) assessing five active treatments: ranibizumab 0.3 mg ( 4 studies, n=1782), ranibizumab 0.5 mg (11 studies, n=3566), bevacizumab 1.25 mg (2 studies, n=882), aflibercebt 0.5 mg (2 studies, n=597), and aflibercebt 2 mg (2 studies, n=1220). Number of patients in placebo group was 294. Mean age of the participants was 76.7 years and 57% were women.

Visual aquity, letters gained (%) compared to placebo

Ranibizumab 0.3 mg: 2.39% (95% confidence interval (CI) 1.59-3.19; p<0.001)

Ranibizumab 0.5 mg: 3.56% (2.58-4.13; p<0.001)

Bevacizumab 1.25 mg: 2.14% (0.47-3.82; p0.012)

Aflibercept 0.5 mg: 2.91% (0.99-4.82; p=0.003)

Aflibercept 2 mg: 3.44% (1.73-5.14; p<0.001).

  • Tutkimuksen laatu: kelvollinen
  • Sovellettavuus suomalaiseen väestöön: kohtalainen

Tämä teksti on linkitetty seuraaviin artikkeleihin:

  • Kostea silmänpohjan ikärappeuma (AMD) 1

Kommentti: Puutteellisen raportoinnin vuoksi tutkijat ovat imputoineet joitakin arvoja. Vertailu lumeeseen perustuu kahden pienen tutkimuksen lumeryhmiin. Afliberseptin osalta tulokset perustuvat edellä esitettyihin VIEW1- ja -2 tutkimusten tuloksiin «Heier JS, Brown DM, Chong V ym. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119:2537-48 »1.

Kirjallisuutta

  1. Heier JS, Brown DM, Chong V ym. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012;119:2537-48 «PMID: 23084240»PubMed
  2. Yuzawa M, Fujita K, Wittrup-Jensen KU ym. Improvement in vision-related function with intravitreal aflibercept: data from phase 3 studies in wet age-related macular degeneration. Ophthalmology 2015;122:571-8 «PMID: 25439429»PubMed
  3. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF ym. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology 2014;121:193-201 «PMID: 24084500»PubMed
  4. Schmid MK, Bachmann LM, Fäs L ym. Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis. Br J Ophthalmol 2015;99:141-6 «PMID: 25271911»PubMed
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