{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T07:43:16Z","timestamp":1776930196790,"version":"3.51.2"},"reference-count":3,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T00:00:00Z","timestamp":1744588800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T00:00:00Z","timestamp":1744588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000615","name":"Fight for Sight UK","doi-asserted-by":"publisher","award":["2036 \/ 2037"],"award-info":[{"award-number":["2036 \/ 2037"]}],"id":[{"id":"10.13039\/501100000615","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"abstract":"Abstract<\/jats:title>\n \n Background<\/jats:title>\n The vitrectomy, subretinal Tissue plasminogen activator and Intravitreal Gas for submacular haemorrhage secondary to Exudative Age-Related macular degeneration (TIGER) trial is a pan-European, two-group, non-commercial, active-control, observer-masked, superiority, randomised controlled surgical clinical trial of an investigational medicinal product.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n The original protocol for this trial was published on 31 January 2022 (https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-021-05966-3<\/jats:ext-link>). This update reports on key changes in the study protocol in version 2.0 which was approved for trial sites from 18 January 2022, and the current version 3.0 which was approved for trial sites from 25 April 2023, and includes current versions of the statistical analysis plan and health economics analysis plan. In summary, there have been changes to three eligibility criteria: removing the word \u201cActilyse\u201d from exclusion criterion 2, updating exclusion criterion 5 to state abstinence from heterosexual intercourse or the use of highly effective methods of birth control is mandatory for up to 12\u00a0weeks after last aflibercept exposure on trial, and clarifying exclusion criterion 6 relating to international normalised ratio (INR) is only applicable to participants receiving warfarin. Changes to secondary outcomes include Radner Reading speed being limited to the study eye only, and moving EQ-5D-5L from a secondary reported efficacy outcome to a component of health economic analysis reporting only. Actilyse Cathflo was added as an additional permitted investigational medicinal product as this is already used in practice in the UK and is molecularly identical to Actilyse 10\u00a0mg. Instructions were added to account for participants who had already been exposed to aflibercept or a similar anti-vascular endothelial growth factor (anti-VEGF) within 21\u00a0days (the minimum window between anti-VEGF treatments permitted on trial) prior to study enrolment, storage of tissue plasminogen activator in theatre and operating room environments, and the recording of additional, as-needed aflibercept treatments in-between study visits at the discretion of the study investigator. Finally, sections and subsections have been added to detail the imaging analysis plan, patient public involvement plan, INR testing, and recruitment and informed consent components of the trial. The primary analysis of the trial as stated in the statistical analysis plan is the difference between groups in the proportion of participants gaining\u2009\u2265\u200910 ETDRS letters in their study eye at the month 12 visit, whilst the primary health economic analysis of the trial is the difference in quality-adjusted life years between groups at 12\u00a0months.<\/jats:p>\n <\/jats:sec>\n \n Trial registration<\/jats:title>\n ClinicalTrials.gov identifier: NCT04663750<\/jats:ext-link>; EudraCT: 2020\u2013004917-10.\u00a0<\/jats:p>\n <\/jats:sec>","DOI":"10.1186\/s13063-025-08727-8","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T03:25:07Z","timestamp":1744601107000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Vitrectomy, subretinal Tissue plasminogen activator and Intravitreal Gas for submacular haemorrhage secondary to Exudative Age-Related macular degeneration (TIGER): update to study protocol and addition of a statistical analysis plan and health economic analysis plan for a randomised controlled surgical trial"],"prefix":"10.1186","volume":"26","author":[{"given":"Chan Ning","family":"Lee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Riti","family":"Desai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa","family":"Ramazzotto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hatem","family":"Wafa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanzhong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catey","family":"Bunce","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kodchawan","family":"Doungsong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victory","family":"Ezeofor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rhiannon T.","family":"Edwards","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noemi","family":"Lois","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David H.","family":"Steel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tunde","family":"Peto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jost","family":"Hillenkamp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan C.","family":"van Meurs","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Barnaby C.","family":"Reeves","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy L.","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,4,14]]},"reference":[{"issue":"1","key":"8727_CR1","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1186\/s13063-021-05966-3","volume":"23","author":"TL Jackson","year":"2022","unstructured":"Jackson TL, Bunce C, Desai R, Hillenkamp J, Lee CN, Lois N, et al. Vitrectomy, subretinal tissue plasminogen activator and intravitreal gas for submacular haemorrhage secondary to exudative age-related macular degeneration (TIGER): study protocol for a phase 3, pan-European, two-group, non-commercial, active-control, obs. Trials. 2022;23(1):99.\u00a0Available from:\u00a0https:\/\/doi.org\/10.1186\/s13063-021-05966-3.","journal-title":"Trials."},{"key":"8727_CR2","unstructured":"The European Stroke Organisation. European Stroke Organisation Letter 3 on the Shortage of Actilyse. 2023. Available from: https:\/\/eso-stroke.org\/wp-content\/uploads\/3.Letter_Tenecteplase_Shortage_20221219.pdf."},{"key":"8727_CR3","unstructured":"Bayer PLC. Eylea 40mg\/ml solution for injection in a vial - Summary of Product Characteristics (SmPC). emc. 2021. Available from: https:\/\/www.medicines.org.uk\/emc\/product\/2879\/smpc#DOCREVISION. Cited 2021 Nov 15."}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-025-08727-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13063-025-08727-8\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-025-08727-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,4]],"date-time":"2025-05-04T17:17:51Z","timestamp":1746379071000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-025-08727-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,14]]},"references-count":3,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["8727"],"URL":"https:\/\/doi.org\/10.1186\/s13063-025-08727-8","relation":{},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,14]]},"assertion":[{"value":"11 December 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 January 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 May 2025","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"For protocol v3.0 a version that included comments and tracked changes was originally published.","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"TIGER has obtained a favourable opinion from the Cambridge East Research Ethics Committee REC (20\/EE\/0293) and Health Research Authority (HRA) approval for protocol version 2.0 covering all sites in the UK on 17 January 2022 with full implementation across all sites on 18 January 2022. Protocol version 3.0 received HRA and Health Care Research Wales (HCRW) approval on 12 April 2023 with full implementation across all sites on 25 April 2023. Additional Institutional Review Board approvals will be sought to cover new sites as they join TIGER in continental Europe.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"A trial-specific patient informed consent form (ICF) will be used and has been previously described and included in the original protocol publication supplementary materials (1).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"None of the authors have any financial interest in any licensed TPA products. TJ\u2019s employer receives site payments from Bayer and other commercial entities for participants enrolled on commercial clinical trials of aflibercept and other novel and licensed treatments for wet AMD, and he is a consultant to 2CTech, Alcon, Dutch Ophthalmic Research Centre, iLumen; Opthea, Outlook Therapeutics, Oxurion, Pfizer, and Regeneron and has received conference support from Roche. DS\u2019s employer receives site payments from Bayer and other commercial entities for participants enrolled on commercial clinical trials of aflibercept and other novel and licensed treatments for wet AMD, and he is a consultant to Alcon, Gyroscope, DORC, BVI, Roche, Complement therapeutics, Alimera, and Eyepoint. CNL has undertaken contracting work for Opthea. RD and CNL\u2019s employer has received payments for trials of novel and licensed treatments for wet AMD, including commercial trials of aflibercept. CB\u2019s post is part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London; the views she expresses are her own and not necessarily those of the NIHR or the Department of Health and Social Care. JvM was on the Board of EUREINA when it commissioned Fight for Sight to run the call for funding but left the Board in 2019 before the grant was awarded and was not an applicant on the bid and has no other interests. VE, KD, RTE, LR, HW, YW, NL, TP, JH, and BCR have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"131"}}