Title: A randomised controlled trial of adjunctive intraocular and periocular steroid (triamcinolone acetonide) versus standard treatment in eyes undergoing vitreoretinal surgery for open globe trauma
Funder: Department of Health and Social Care

Abstract: The proposed project is a phase 3, multicentre, randomised clinical trial to test the hypothesis that adjunctive steroid (triamcinolone acetonide) given locally at the time of surgery, can improve the outcome of vitreoretinal surgery for open-globe trauma (both visually and anatomically). Open-globe ocular trauma complicated by intraocular scarring (proliferative vitreoretinopathy, PVR) is a relatively rare, blinding, but potentially treatable, condition for which at present surgery is often unsatisfactory and visual results frequently poor. To date no pharmacological adjuncts to surgery have been proven to be effective. Analysis of the costs and and economic effectiveness of the trial intervention will also be carried out. The lead applicants' team have an established track record of completing and publishing similar large scale randomised controlled clinical trials in vitreoretinal surgery. The project builds on two clinical pilot studies and laboratory investigations suggesting potential efficacy of local steroids and demonstrating the feasibility of a large scale trial. Design: Phase 3 randomised controlled trial Setting: NHS vitreoretinal surgical services Target population: Patients with an open globe injury undergoing vitrectomy either as a primary or secondary procedure. Health technology: The study will compare the effectiveness of (a) vitreoretinal surgery alone (standard treatment) to (b) vitreoretinal surgery with adjunctive local triamcinolone acetonide (trial intervention). The adjunctive medication to be investigated is the per-operative combination of (a) intra-vitreous cavity triamcinolone acetonide 4mg (0.1ml) and (b) sub-tenons capsule (ie peri-ocular) triamcinolone acetonide 40mg (1.0ml). Triamcinolone acetonide is commercially available and is widely used in ocular disease. There are currently no adjunctive anti-scarring treatments which are of proven efficacy in the management of ocular trauma and treatment therefore relies on surgical to repair wounds and retinal detachment and prevent intraocular scarring. The lead applicant has undertaken laboratory investigation indication the potential efficacy of triamcinolone in intraocular scar reduction (Charteris, Lewis, Fisher IOVS, 2008 ARVO supplement, # 4887) A clinical pilot investigation on an anti-inflammatory regime in severe, established PVR (Wickham, Charteris IOVS, 2007 ARVO supplement, # 5740) demonstrated a lack of toxicity and a further pilot investigation is currently underway on the use of triamcinolone in ocular trauma has demonstrated the feasibility of a large scale study. There is now a clear need for definitive data on this adjunctive treatment. Plan of Investigation: This study is a multicentre, prospective, individually randomised, patient -masked, assessor masked controlled trial that will test superiority of the intervention at 6 months. The trial design has been formulated in consultation with the accredited CTU unit at King’s College London, a trial statistician, a methodologist at the Research Design Service, and patients who have suffered severe ocular trauma. 20 vitreoretinal surgery centres throughout the UK have agreed to take part. 300 adult patients with open-globe trauma will be randomised 1:1 to receive adjunctive intraocular and periocular steroid (traimcinolone acetonide) versus standard care (surgery without adjunctive treatment). Operating surgeons will be masked until the end of surgery (when the adjunct is given) patients and outcome observers will be masked throughout. The primary outcome is the corrected visual acuity measured using validated ETDRS vision charts at 6 months (patients were strongly in favour of a visual acuity outcome). The sample size is calculated to show an increase in a meaningful proportion of patients with a clinically meaningful change in visual acuity of 10 letters. Secondary outcomes are the development of scarring (proliferative vitreoretinopathy), retinal detachment, intraocular pressure abnormalities and other complications at 6 months. Quality of life assessments will also be undertaken using the EQ-5D, SF-36 and VFQ25 tools. Using this data cost effectiveness analysis cost-consequence analysis to investigate the impact of injury and recovery will be carried out. Data collection will be undertaken at baseline, three months and six months. Timetable: The project will run until December 2020 : The initial 6 months for project set-up, recruitment will run until March 2020, followed by 6 months final follow-up, then 2 months for write-up and results dissemination. The 28 trial centres have analysed the numbers of cases available for recruitment and this provides a total of 221 per year. A conservative assessment of recruited cases has been taken as 55% of those eligible (recruitment in the pilot study approached 100%) giving a total period to recruit the sample size of 300 cases over the duration of the study. Recruitment will be closely monitored, (an internal pilot phase will be undertaken to allow this) and if there is evidence of under-recruitment alternative strategies such as adding additional study centres will be explored. Trial Management: The overall management structure of this study will consist of Trial Management Group (TMG), Trial Steering Committee (TSC) and a Data Monitoring and Ethics Committee (DMEC). The TMG will be responsible for the day-to-day running and management of the trial. The TSC will be ensure the overall integrity of the study by monitoring progress; investigating adverse events; and taking account of regular reports from the DMEC and TMG. The DMEC will monitor data on recruitment, adverse events, emerging external evidence, sample characteristics and outcomes and make recommendations if any interim analysis is required. Patient and Public Involvement: Patients from our pilot studies have been engaged in the design of the proposed study. These patients and patient groups (Blind Veterans UK and Scottish War Blinded) have agreed to participate in the TSC and TMG and in on-going trial development (eg consent form information sheets, dissemination). Expertise: The research team comprises clinical and statistical researchers at Moorfields Eye Hospital who have a track-record of undertaking and completing similar trials who will work with an experience clinical trials unit at Kings College London and a health economist at Bangor University.

Lay abstract: Eye trauma is a leading cause of blindness and visual impairment. It frequently affects working age people and results in significant time away from work. Penetrating injuries of the eye are more likely to result in poor vision and the main cause of this is a scarring response on the retina (proliferative vitreoretinopathy, PVR). The purpose of this study is to investigate the potential of an anti-inflammatory treatment (triamcinolone acetonide) to improve the outcome of surgery in eyes that have suffered severe trauma. The retina is a thin layer which lines the inside of the eye. It is sensitive to light (like the film in a camera) and is necessary for vision. If a hole or holes develop in a retina it can become detached. Patients whose eyes have suffered severe trauma have a high risk of developing scar tissue on the surface of the retina (proliferative vitreoretinopathy, PVR). This scar tissue pulls on the retina preventing the holes from being repaired by the standard technique used in other retinal detachment patients. If the retina remains detached the eye does not see, can lose its volume and appear unsightly. The study is designed to investigate whether anti-inflammatory medications are a feasible treatment to prevent this scarring response. Currently there are no treatments available to prevent this scarring response. The success rate is limited because the scar tissue often returns, leading to re-detachment. Inflammation is the medical term used to describe the way in which the body reacts to injury. There is good evidence from laboratory studies that additional steroid treatment into and around the eye at the time of surgery could reduce scarring by reducing inflammation and improve visual outcomes. The proposed research is a randomised controlled clinical (RCT) trial to determine if the addition of such steroid medication (triamcinolone acetonide) at the time of surgery for penetrating eye trauma is effective in improving visual and surgical outcomes. An RCT is a research trial in which subjects are randomly assigned to 2 groups: one (the experimental group) receiving the treatment that is being tested, and the other (the comparison group) receiving no treatment or conventional treatment. Participants will be divided in to two equal groups; the study group will receive standard care and the addition of the steroid medication, the control group will receive standard care alone. This means participants will have a 50% chance of receiving the additional study treatment and will not be aware of which group they are in, until the end of the study. Follow up visits and clinical assessments run in parallel with routine clinical care and no additional invasive or time consuming tests are performed. The final assessment is performed at six months after the initial study surgery. The trial is to be coordinated at Moorfields Eye Hospital and will involve 27 other specialist eye surgery units throughout the UK. Treatment success will be measured by an increase in the proportion of patients who have a minimum improvement of 10 letters on visual acuity charts. We have carried out pilot studies on the steroid treatment regime which indicate that the treatment is safe and the study does not involve additional procedures for participating patients. Our research team has an established track record of completing similar large-scale studies and the research unit at Moorfields together with the clinical trials unit at Kings College Hospital, London have extensive experience of clinical trials involving multiple centres. We will work with the health economics unit at Bangor University, who also have experience of vision-loss related trials to evaluate the economic and cost-effectiveness aspects of the proposed new treatment. A study involving multiple sites, with a dedicated research team over a four year period is required to recruit sufficient surgical eye trauma cases to provide a large enough study to test the effectiveness of the treatment – analysis of the frequency of cases at the study centres has indicated that adequate numbers will be available for the study to be successfully completed in the proposed time scale. The results of the study will be disseminated via medical journals, professional meetings and relevant patient groups.

Research activity codes: 6.1 PHARMACEUTICALS;6.4 SURGERY
Health categories: EYE