Title: Five year observational follow-up of the IVAN trial cohort: a study of function and morphology
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: The IVAN cohort extension study is designed to answer additional research questions of major importance to the NHS about the management of neovascular age-related macular degeneration (nAMD) in the longer term. The IVAN study which enrolled 610 participants with neovascular (nAMD) age-related macular degeneration was closed in October 2012 when all remaining participants had completed two full years of follow up. In IVAN participants were randomised to one of two drugs (ranibizumab or bevacizumab and two re-treatment regimens monthly or discontinuous). The study has reported its main findings and showed that the two drugs had similar efficacy for the primary outcome of best corrected distance visual acuity after two years of follow up. Monthly treatment was neither inferior nor non inferior to discontinuous treatment. nAMD is a chronic disease and despite two years of therapy during the trial it was anticipated that almost all would require regular assessments after exiting the trial in order to ensure that any continuing need for re-treatment was met. Therefore after the 24 month visit the IVAN study teams at each site, transferred participants to the locally established NHS macular services for assessment and re-treatment of neovascular AMD. Emerging clinical information indicates that many patients will continue to develop additional functional deficits with losses of acuity despite treatment with antiVEGF agents beyond year 2. Studies of structure and function of the retina in nAMD eyes receiving antiVEGF therapy indicate that fibrosis and atrophy are key determinants of worsening vision. AntiVEGF agents would therefore appear to be incapable of preventing fibrosis. In addition the chronic inhibition of VEGF in the environment of posterior fundus is thought to have the potential to switch off the growth promoting and maintenance roles of VEGF protein; and a consequence of this may be progression to atrophy. None of the clinical trials undertaken thus far have extended beyond two years. Despite the several comparative effectiveness clinical trials that have either completed (CATT in the USA and MANTA in Austria) or are about to report (GEFAL), none have plans to investigate long term outcomes. Two open-label industry-sponsored studies following up participants in trials carried out to support marketing authorisations for ranibizumab have been reported, namely HORIZON (following up participants in the ANCHOR, MARINA and FOCUS trials) and SECURE (following up participants in the SUSTAIN and EXCITE trials). They observed a decrease in the visual acuity benefit of ranibizumab in the long term, but did not identify the cause of the decrease. We hypothesize that atrophy of the macular tissues which is a component of the disease process itself but could also be accentuated and accelerated by antiVEGF treatment . Furthermore, the findings of HORIZON and SECURE are of limited value as they do not address objectives of importance within the UK setting: (i) treatment during follow-up was not consistent with current treatment provision in the NHS, i.e. regular review and retreatment based on ocular coherence tomograms (OCTs), (ii) treatment in the initial trials was all ‘continuous’ (monthly), (iii) there was either low recruitment to the follow-up studies (<40% in SECURE) or high attrition during follow up (>30% amongst recruits to the follow-up studies in HORIZON); (iv) the primary objective of both studies was to document long term safety. Nevertheless, their findings that visual acuity gains during the initial trials were largely lost over the longer term highlight the importance of extending follow-up for IVAN trial participants. In the UK the establishment of dedicated macular service clinics to provide treatment with antiVEGF agents in nAMD has been implemented widely throughout the NHS. IVAN study participants were subsumed into the local clinical services and have continued to access treatment in the NHS. Therefore the IVAN investigators proposed an extension to systematically extract the accrued clinical information on ex IVAN participants and to also perform a single study visit assessment at which a structured clinical and morphologically evaluation of the posterior retina would be performed. The IVAN extension would therefore obtain data that would allow the analysis of structure and functional relationships in the context of the history of treated nAMD and provide insights into the causes of continuing vision loss in years 3 to 5 after the initiation of treatment.

Lay abstract: The IVAN trial treated patients with neovascular age-related macular degeneration (nAMD) from diagnosis with one of two different drugs and also compared two different regimens. Patients were followed up for a period of 2 years. On completion of the study participants have undergone regular follow-up and review in NHS eye clinics as the eye condition is not cured by the treatment and long term follow up and clinical care is required. The proposed study aims to gather data on the eyesight outcomes of IVAN participants from years 3 to 5, the number of treatments that were administered after leaving the trial and the condition of the macula of the eye. These data will help inform healthcare planners on the necessity for long-term care, the frequency of review and follow-up and whether these are dependent on the drug or treatment regimens that were tested in the IVAN trial.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: EYE