英国国家健康研究院Sobha Sivaprasad团队研究了阿柏西普不同剂量注射治疗糖尿病黄斑水肿的疗效与安全性。2024年3月7日出版的《柳叶刀》杂志发表了这项成果。

玻璃体内大剂量注射阿柏西普（8 mg）可通过比标准对照品阿柏西普2 mg 更少的注射次数来改善糖尿病黄斑水肿（DMO）的治疗结果。研究组报道了8 mg与2 mg阿柏西普治疗DMO患者的疗效和安全性结局。

PHOTON是一项随机、双盲、非劣效性的2/3期临床试验，在7个国家的138家医院和专业视网膜诊所进行。符合条件的患者是18岁及以上患有1型或2型糖尿病的成年人，伴有中心累及DMO。在最初的每月给药后，患者被随机分为（1:2:1）玻璃体内注射2 mg每8周一次（2q8）、8 mg每12周一次（8q12）或8 mg每16周一次（8q16）。

从第16周开始，如果患者符合表示疾病活动性的预先指定的剂量方案修改标准，则缩短8 mg阿柏西普组的给药间隔。主要终点是第48周的最佳矫正视力（BCVA）与基线相比的变化（非劣效范围为4个字母）。疗效和安全性分析包括所有随机分配的至少接受一剂研究治疗的患者。

在2020年6月29日至2021年6月28日期间，970名患者接受了资格筛查。排除后，660名患者被纳入并随机分配接受阿柏西普8q12（n=329）、8q16（n=164）或2q8（n=167）；两名患者被错误地随机分配，没有接受治疗。658名（99.7%）患者接受了治疗，并纳入完整分析集和安全性分析集（8q12 n=328、8q16 n=163和2q8 n=167）。患者平均年龄为62.3岁（SD 10.4）。401例（61%）患者为男性。471名（72%）患者为白人。

阿柏西普8q12和8q16的BCVA增益不低于阿非利西普2q8（8q12组的BCVA平均值从基线变化为8.8个字母[SD 9.0]，8q16组为7.9个字母[8.4]，2q8组为9.2个字母[9.0]）。最小二乘平均值的差异在8q12和2q8之间为–0.57个字母（95%CI–2.26至1.13，非劣效性p值＜0.0001），在阿柏西普8q16和2q8之间为–1.44个字母（–3.27至0.39，非劣性p值0.0031）。研究眼中发生眼部不良事件的患者比例在各组之间相似（8q12 n=104[32%]、8q16 n=48[29%]和2q8 n=46[28%]）。

研究结果表明，阿柏西普8mg在延长给药间隔的情况下显示出有效性和安全性，并可降低DMO患者的治疗负担。

附：英文原文

Title: Intravitreal aflibercept 8 mg in diabetic macular oedema (PHOTON): 48-week results from a randomised, double-masked, non-inferiority, phase 2/3 trial

Author: David M Brown, David S Boyer, Diana V Do, Charles C Wykoff, Taiji Sakamoto, Peter Win, Sunir Joshi, Hani Salehi-Had, András Seres, Alyson J Berliner, Sergio Leal, Robert Vitti, Karen W Chu, Kimberly Reed, Rohini Rao, Yenchieh Cheng, Wei Sun, Delia Voronca, Rafia Bhore, Ursula Schmidt-Ott, Thomas Schmelter, Andrea Schulze, Xin Zhang, Boaz Hirshberg, George D Yancopoulos, Sobha Sivaprasad, Prema Abraham, Christopher Aderman, Kunihiko Akiyama, Daniel V. Alfaro, Fareed A. Ali, Payam Amini, Andres Emanuelli Anzalotta, Gyrgy Bátor, Ivan Batlle, Adam Berger, Ramanath Bhandari, William Bridges, Christian Brinkmann, Jamin Brown, Stuart Burgess, Jorge Calzada, Antonio Capone Jr., Dana Cervena, Steven Charles, Nauman Chaudhry, David Chow, W. Lloyd Clark, Paul Conrad III, Matthew Cunningham, Hajir Dadgostar, Amr Dessouki, Dana Deupree, Christopher Devine, David Eichenbaum, Jan Ernest, Nicolas Feltgen, Moss Fenberg, Philip Ferrone, Ronald Frenkel, Scott Friedman, Julie Gasperini, Adam Gerstenblith, Ghassan Ghorayeb, Michel Giunta, Mitchell Goff, Liliya Golas, Joseph M. Googe Jr., Jordana Goren Fein, Curtis Hagedorn, Akira Hagiwara, Paul Hahn, Richard Hairston, Jason Handza, Vivienne Hau, Ken Hayashi, Jeffrey Heier, Vrinda Hershberger, Patrick Higgins, Yoshio Hirano, Shigeru Honda, Yasuko Ikegami, Yuichiro Ishida, Isao Ishikawa, Kiyoshi Ishii, Eric P. Jablon, Atul Jain, Yuichi Kaji, Kapil Kapoor, ágnes Kerényi, Kazuhiro Kimura, Genichiro Kishino, Katalin Kiss, Takashi Kitaoka, James M. Klancnik, Namie Kobayashi, Jiro Kogo, Vladimir Korda, Erik Kruger, Sentaro Kusuhara, Wilfredo Lara, Ketan Laud, Seong Lee, James Luu, Dennis Marcus, Calvin Mein, Annal Meleth, Tibor Milibák, Yoshinori Mitamura, Toshinori Murata, Sumiyo Noge, Hajime Onoe, James Osher, András Papp, Justin Parschauer, Sugat Patel, Sunil Patel, Matthew Pezda, Ashkan Pirouz, Pradeep Prasad, Omar Punjabi, Llewelyn Rao

Issue&Volume: 2024-03-07

Abstract:

Background

A high-dose formulation of intravitreal aflibercept (8 mg) could improve treatment outcomes in diabetic macular oedema (DMO) by requiring fewer injections than the standard comparator, aflibercept 2 mg. We report efficacy and safety results of aflibercept 8 mg versus 2 mg in patients with DMO.

Methods

PHOTON was a randomised, double-masked, non-inferiority, phase 2/3 trial performed at 138 hospitals and specialty retina clinics in seven countries. Eligible patients were adults aged 18 years or older with type 1 or 2 diabetes and centre-involved DMO. Patients were randomly assigned (1:2:1) to intravitreal aflibercept 2 mg every 8 weeks (2q8), aflibercept 8 mg every 12 weeks (8q12), or aflibercept 8 mg every 16 weeks (8q16), following initial monthly dosing. From week 16, dosing intervals for the aflibercept 8 mg groups were shortened if patients met prespecified dose regimen modification criteria denoting disease activity. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48 (non-inferiority margin of 4 letters). Efficacy and safety analyses included all randomly assigned patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT04429503).

Findings

Between June 29, 2020, and June 28, 2021, 970 patients were screened for eligibility. After exclusions, 660 patients were enrolled and randomly assigned to receive aflibercept 8q12 (n=329), 8q16 (n=164), or 2q8 (n=167); two patients were randomly assigned in error and did not receive treatment. 658 (99·7%) patients were treated and included in the full analysis set and safety analysis set (8q12 n=328, 8q16 n=163, and 2q8 n=167). Mean patient age was 62·3 years (SD 10·4). 401 (61%) patients were male. 471 (72%) patients were White. Aflibercept 8q12 and 8q16 demonstrated non-inferior BCVA gains to aflibercept 2q8 (BCVA mean change from baseline 8·8 letters [SD 9·0] in the 8q12 group, 7·9 letters [8·4] in the 8q16 group, and 9·2 letters [9·0] in the 2q8 group). The difference in least squares means was –0·57 letters (95% CI –2·26 to 1·13, p value for non-inferiority <0·0001) between 8q12 and 2q8 and –1·44 letters (–3·27 to 0·39, p value for non-inferiority 0·0031) between aflibercept 8q16 and 2q8. Proportions of patients with ocular adverse events in the study eye were similar across groups (8q12 n=104 [32%], 8q16 n=48 [29%], and 2q8 n=46 [28%]).

Interpretation

Aflibercept 8 mg demonstrated efficacy and safety with extended dosing intervals and could decrease treatment burden in patients with DMO.

DOI: 10.1016/S0140-6736(23)02577-1

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)02577-1/abstract