Award Title: Early Vitrectomy and Intravitreal Antibiotics for post-operative exogenous eNdophthalmitis (EVIAN) study: A feasibility multicentre randomised controlled trial
Funder: Department of Health and Social Care

Abstract: Research question   To explore the feasibility and acceptability of carrying out a randomised clinical trial of early surgical treatment compared to standard treatment for endophthalmitis.     Background   Primary Objectives:   To assess the recruitment and retention rates of participants,willingness of surgeons to refer patients into the study,and willingness of participants to be randomised.     Secondary objectives:  To report mean (SD) visual acuity gain from randomisation to 6 months after randomisation as measured using an ETDRS chart at a starting distance of 4 metres in patients treated with early vitrectomy and with standard treatment, and to report the mean difference with 95 % confidence intervals.   To assess the safety of early vitrectomy plus intravitreal antibiotics versus standard of care.     Methods   This is a multicentre,national clinical trial with 1:1 randomisation and control group.    Follow-up period:6 months.     Ophthalmic Entry Criteria:   Symptomatic visual loss attributable to newly-diagnosed postoperative,exogenous endophthalmitis.   Best corrected vision worse than 35 ETDRS letters in the study eye     We will recruit 70 patients: 35 patients allocated to each study arm.   We estimate our expected 70% recruitment rate (95%CI:60-80) will be achieved if 105 eligible patients with acute endophthalmitis are approached.   Twenty UK sites have confirmed participation,committing total of 250 endophthalmitis participants over 21-month recruitment period.     Timelines for delivery (start adjusted/delayed due to Covid-19 pandemic)   Start:March 1st 2021  End:March 1st 2024     Months 1-6: Staff recruitment/support,document development,obtaining regulatory approvals (ethics,R&D approvals),setting up trial management,randomisation systems,trial databases,and constituting trial management group (TMG).     Months 7-27: Site initiation and training planned for months 4-12.   Recruitment of trial participants will run between months 7-27 lasting 21 months,with trial intervention and follow-up assessments completed within timelines.   Data entry/data cleaning will be a continuous process.     Months 27-30: Final follow-up assessments;final data entry;data cleaning, and database lock. Final trial steering committee/TMG meetings.     Months 31-36: Data analysis and report writing;Dissemination of trial report     Anticipated Impact and Dissemination   Impact   The role of early vitrectomy for any type of exogenous endophthalmitis remains unproven.The absence of evidence for patient treatment has led to lack of consensus among clinicians with unacceptably wide variations in clinical practice regarding thresholds of visual acuity to surgically intervene,and timings of vitrectomy operation after initial non-response to antibiotic eye injections.   Study outcomes will enable development of a full clinical trial that will aim to improve evidence-based guidelines,and reduce the socioeconomic burden and NHS management costs provided that feasibility is shown and a promising signal of efficacy.     Dissemination   We aim to publish study results in peer-reviewed journals and present results at national/ international clinical meetings (in particular,Royal College of Ophthalmologists,European Society of Retina Specialists,BEAVRS).One patient co-applicant will co-present study findings alongside principal investigators at a UK meeting.   The patient advisory group (PAG) will create a lay Results summary for research participants,and assist with results disseminating to non-professional audiences (Moorfields/BRC websites) and Moorfields Patient Involvement Days.The Royal National Institute of Blind People (RNIB) have agreed to webpost recruitment calls, and disseminate trial results on RNIB website/networks to promote uptake by NHS users.Results disseminated to trial centres for discussion at local and regional clinical governance meetings.

Lay Abstract: What is this study about?   To assess the feasibility of doing a trial of the benefit of prompt surgery for a rare but blinding bacterial infection known as “endophthalmitis,”which can complicate invasive eye procedures. Endophthalmitis causes rapid loss of vision. Antibiotic injections may not be sufficient to control the infection and up to 50% patients need surgery to remove the infected vitreous (vitrectomy).      Usual care involves intensive and extended inpatient and outpatient management over a 6-month period. The impact on the well being of patients and their carers, both physically and psychologically, is immense often with severe pain and sight loss, which may or may not recover. It is usually managed in specialist tertiary centres at very considerable cost to the NHS recently estimated by the RNIB as much as £1 million annually.       How will this study help patients?   Earlier surgery, by removing infected vitreous material at diagnosis rather than after failure to respond to intravitreal antibiotics, may accelerate recovery from the infection. Early vitrectomy may improve vision recovery, patient well-being, reduce NHS and patient costs with less hospital visits, and assist in endeavours to reduce antibiotic usage.     What will we do in this Study?   In order to measure the possible benefit of earlier surgery, we need to conduct a feasibility study of a multicentre randomised controlled trial. The complication is rare, and patients and their carers are severely shocked and emotionally distressed by its occurrence. So we need to discover if the trial we are planning is possible in the reality of urgent care management of these people in current NHS environments. This includes whether both patients and their surgeons can be recruited.     We will keep the study simple but key components include close involvement of patient advisors to ensure participant experience during this traumatic time is handled as sensitively as possible.The Health Economic component is to assess whether the relative cost and benefit of earlier surgery could be assessed in a definitive study.     Participants will be randomly allocated to vitrectomy performed at an earlier stage of the condition, or later if needs be in accordance with standard care. Standard follow-up for both arms will continue until stable.     What do our patients think about the study?   We undertook a focus group and interviews with patients who had vitrectomy for endophthalmitis exploring their views and experiences. The consensus was the study was worthwhile. They advised us to approach study patients in an undisturbed environment with nursing support, giving them at least 48 hours to reflect on trial information. We have modified the study design to implement this. Based on their advice, we plan patient advisory group meetings during the study to guide our research. Two co-applicants are previous endophthalmitis patients.

Research Activity Codes: 6.4 SURGERY
Health Categories: EYE