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

BACKGROUND: 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.

METHODS: The original protocol for this trial was published on 31 January 2022 ( https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-021-05966-3 ). 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 "Actilyse" 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 weeks 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 mg. 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 days (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 ≥ 10 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 months.

TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04663750 ; EudraCT: 2020-004917-10.