Two phase-3 studies (VIEW 1, VIEW 2) «Heier JS, Brown DM, Chong V ym. Intravitreal aflib...»1, «Yuzawa M, Fujita K, Wittrup-Jensen KU ym. Improvem...»2 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 for 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=1 217 and VIEW 2 n=1 240) 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 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. Endpoint assessment was performed every 4 weeks. Both full analysis and per protocol analysis were conducted. The drop-out rate for combined aflibercept groups were 7.1% (VIEW1) and 10.7% (VIEW2). The respective figures for ranibizumab group was 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. In integrated analysis of the two studies all aflibercept regimens produced similar improvements in anatomic measures.
Number (percentage) of patients with at least 1 ocular serious adverse event was 10 (3.3) for Rq4 group, 7 (2.3) for 2q4 group, 6 (2.0) for 0.5q4 group and 2 (1.0) for 2q8 group in VIEW 1 study. The figures in VIEW 2 study were 9 (3.1), 6 (1.9), 5 (1.7), and 9 (2.9), respectively. The combined data for both studies showed a rate of treatment-emergent serious adverse events (eye disorders, endophthalmitis, procedural complications, and increased intraocular pressure) per1000 injections of 1.1, 0.8, 0.1, and 0.2 for the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively. Overall incidence of serious systemic adverse events (range VIEW 1 13.2–18.8% and VIEW 2 8.9–12.5%), specific arterial thromboembolic end points as set forth by the Anti-Platelet Trialists' Collaboration (range VIEW 1 0.7–2.3% and VIEW 2 1.3–2.6%), and deaths was similar between aflibercept and ranibizumab. Among the aflibercept treatment groups, there was no evidence of a dose-response for adverse events.
Kommentti: VIEW1-tutkimuksen populaatiosta yli 95% oli valkoihoisia, VIEW2-tutkimus suoritettiin osin Euroopassa, mukana oli noin 20% aasialaisia. Tutkimuksen päätetapahtumissa ei ilmoiteta turvallisuusmittareita, vaikka ne raportoitiin. Tilastollista testausta ei raportoitu haittatapahtumien osalta. Tutkimusta sponsoroivat Regeneron Pharmaceuticals ja Bayer HealthCare. Sponsorit osallistuivat tutkimuksen suunnitteluun, tulosten analysointiin ja käsikirjoituksen laatimiseen.
The purpose of the study «Schmidt-Erfurth U, Kaiser PK, Korobelnik JF ym. In...»3 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.
The study is a follow-up for VIEW 1 and VIEW 2 studies «Heier JS, Brown DM, Chong V ym. Intravitreal aflib...»1, therefore methods are described in 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 2 235 patients entered the follow-up study and 2 063 (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 conjunction 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. Mean BCVA gains were 8.3 to 9.3 letters at week 52. At week 96 gains 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.
Most common ocular adverse events were conjunctival hemorrhage (range 23.7–29.9%), retinal hemorrhage (13.6–16.2%), reduced visual acuity (11.3–13.0%), eye pain (8.9–12.1%), vitreous detachment (7.7–10.0%), and increased intraocular pressure (6.2–10.8%) from baseline to week 96. Intraocular inflammation was reported for 1.5%, 1.1%, 0.8%, and 0.5% for Rq4, 2q4, 0.5q4 and 2q8 groups. Serious ocular adverse events occurred for 4.4%, 3.6%, 3.2%, and 3.9%, respectively. The figures for serious non-ocular adverse events were 24.5%, 21.4%, 25.3%, and 25.2%. These events included atrial fibrillation, myocardial infarction, pneumonia, fall, congestive heart failure, coronary artery disease, TIA, cerebrovascular accident, COPD and osteoarthritis. Percentage of specific arterial thromboembolic end points as set forth by the Anti-Platelet Trialists' Collaboration was 3.2% for Rq4 group and 2.4% for 2q4, 3.8% for 0.5q4, and 3.6% for 2q8. The percentage of nonfatal myocardial infarction ranged from 1.0 to 2.0% and nonfatal stroke from 0.5 to 0.8%. The percentage of deaths was 2.7%, 2.1%, 3.2%, and 3.3% for the groups.
Kommentti: VIEW1-tutkimuksen populaatiosta yli 95% oli valkoihoisia, VIEW2-tutkimus suoritettiin osin Euroopassa, mukana oli noin 20% aasialaisia. Tutkimuksen päätetapahtumissa ei ilmoitettu turvallisuusmittareita, vaikka ne raportoitiin. Tilastollista testausta ei raportoitu haittatapahtumien osalta. 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 adv...»4aimed 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 (8 341 patients) assessing five active treatments: ranibizumab 0.3 mg ( 4 studies, n=1 782), ranibizumab 0.5 mg (11 studies, n=3 566), bevacizumab 1.25 mg (2 studies, n=882), aflibercebt 0.5 mg (2 studies, n=597), and aflibercebt 2 mg (2 studies, n=1 220). Number of patients in placebo group was 294. Mean age of the participants was 76.7 years and 57% were women.
Compared with placebo, all study treatments had a significantly higher percentage of letters gained. Compared with placebo, serious side effects were higher in all active treatments: ranibizumab 0.3 mg 4.41% (95% confidence interval (CI) 3.42–5.40; p<0.001), ranibizumab 0.5 mg 5.33%(4.37–6.30; p<0.001), bevacizumab 1.25 mg 5.58% (3.567–7.6), aflibercept 0.5 mg 5.65% (3.28–8.02; p<0.001) and aflibercept 2 mg 5.29% (3.18–7.39; p<0.001). Compared with placebo, systemic thrombotic events occurred for 3.6% (2.69–4.56; p<0.01), 3.94% (3.02–4.86; p<0.001), 4.12% (2.27–5.97), and 3.94% (1.03–6.84; p=0.008), respectively. An estimate for aflibercept 2 mg could not be calculated. In the network analysis relationship between efficacy and serious side effects was assessed.
Kommentti: Joidenkin mukana olevien tutkimusten raportoinnin puutteellisuuden vuoksi tutkijat ovat imputoineet joitakin arvoja. Vertailu lumeeseen perustui kahden pienen tutkimuksen lumeryhmiin. Afliberseptin osalta tulokset perustuivat edellä esitettyihin VIEW1- ja -2-tutkimusten tuloksiin «Schmid MK, Bachmann LM, Fäs L ym. Efficacy and adv...»4.