Treatment of Retinal Detachment in People Who Have Not Had Cataract Surgery With Vitrectomy vs Vitrectomy and Cataract Removal

Background Rhegmatogenous retinal detachment (RRD) is the separation of the retina from the wall of the eye, where it is normally attached. It affects 10-18 people per 100,000 per year. Thus, in the UK, with a population of around 68 million, there are 6700-12,000 RRD per year.

RRD can lead to permanent central and peripheral vision loss (i.e. total blindness) if not treated in a timely manner. Vitrectomy is the most common surgery done for RRD. Retinal reattachment following one vitrectomy occurs in 80-88% of eyes, with 59-67% gaining vision above 0.3 LogMAR, which is the vision required to fulfil UK driving standards.

Data from the British and Eire Association of Vitreo-Retinal Surgeons (BEAVRS) showed that most patients with RRD are phakic: they still have their natural lens (i.e. have not had cataract surgery). Data from the BEAVRS database (unpublished, but accessible to the COMBAT research group) showed that of 8436 vitrectomies done in non-high myopic phakic eyes out of 13,900 vitrectomies performed at several sites in the UK, only 10% combined vitrectomy with cataract surgery (called phacovitrectomy) at the time of the RRD repair. Of 664 phakic eyes with at least 12 months follow-up in which combined surgery was not performed at the time of RRD surgery, 320 (48%) were recorded to have a cataract or to have had it already removed within three months of the original vitrectomy. Only 20% of these eyes had their own clear natural lens at 12 months following vitrectomy. Therefore, phacovitrectomy is done in a minority of patients at the time of RRD repair; and many patients have either a cataract present or undergo separate cataract surgery soon after the RRD surgery.

Previous studies have shown the potential benefits of doing combined RRD and cataract surgery. If the cataract is removed when the RRD is repaired, the view of the back of the eye may be clearer, because the surgeon will see through the clear artificial lens. The purpose of the vitrectomy is to remove the vitreous, which is a gel-like structure that fills the back of the eye. The vitreous is involved in the occurrence of the RRD and, given that the vitreous is also present around the posterior part of the lens of the eye, removing the lens allows a more thorough removal of the vitreous. This has the potential to improve the anatomical outcome of the vitrectomy (i.e. reattachment of the retina) and reduce the number of surgeries required because there would be less need for reoperations (repeated vitrectomies) if the first vitrectomy fails to put the retina back in place. Phacovitrectomy would also obviate the need to do the cataract surgery at a later time following the vitrectomy. Adding a phaco to the vitrectomy will add approximately 8 minutes to the surgical time but could save 6000 cataract surgeries per year to the NHS. Moreover, when cataract surgery is done after vitrectomy, the vitreous is no longer present and there is less support to the lens. This may make the cataract surgery more difficult and increase the risk of intraoperative complications.

However, some studies have suggested that postoperative inflammation, accumulation of fluid in the centre of the retina (cystoid macular oedema), epiretinal membrane formation, and posterior synechiae (adherence of the iris to the intraocular lens) may be more frequent after phacovitrectomy. Calculation of the required artificial intraocular lens, which is used to replace the natural lens of the eye during cataract surgery, may be less accurate when doing combined phacovitrectomy in eyes where the macula (i.e. the central retina) is detached. This is because the calculation of the intraocular lens requires measuring the length of the eye and this is less accurate if the macula is detached. However, errors appear to depend on the technique used for this calculation. A less accurate measure of the intraocular lens would mean people may need glasses to improve their vision following surgery.

Rationale for the Study Previous studies comparing vitrectomy with phacovitrectomy in people with RRD have been mostly retrospective and small, with methodological weaknesses. None have addressed patient reported outcomes, patient views and acceptability for one surgery over the other, or costs.

Two systematic reviews of phacovitrectomy versus vitrectomy and subsequent cataract surgery have been published recently. Farahvash et al. included studies in which vitrectomy or phacovitrectomy were used for a variety of retinal disorders, including RRD, macular hole, epiretinal membrane, and others. They included six retrospective before and after studies and one prospective study on RRD but no randomised trials. Results for the RRD group were not given separately. The Mirshahi et al. review included studies specifically comparing surgeries in people with RRD. The review included five retrospective before and after studies, one study defined as a "quasi randomised" and one randomised trial. Only one of the studies included in the review by Mirshahi et al. was in the Farahvash et al. review. The randomised trial in Mirshahi et al. review was a small poorly reported study with 59 patients (59 eyes) randomised to vitrectomy alone (n=29) or phacovitrectomy (n=30). Although not clearly stated, the trial seems to have been a non-inferiority trial with a non-inferiority margin of 10% or less between groups for the primary outcome (retinal reattachment with a single surgery at 6 months). However, a 10% difference in single surgery success on retinal re-attachment seems clinically important. The authors stated that, accepting a 5% type 1 error and 80% power, a sample size of 50 eyes would be needed to detect differences between groups in the primary outcome. Secondary outcomes included final best-corrected visual acuity (BCVA), intraocular pressure, central macular thickness, and progression of cataract in the vitrectomy only group. Mora et al. stated that all outcomes (primary and secondary) were assessed at 1 week and 1, 3 and 6 months after surgery. The trial found no differences in outcomes at six months postsurgery except progression of cataract in the vitrectomy group. Patient reported outcomes and patient experience and acceptability, intra and post-operative complications and costs were not systematically evaluated.

Authors of both systematic reviews called for randomised trials to determine the best surgical approach for people with phakic RRD. COMBAT is such a trial.

Rationale for the Intervention Phacovitrectomy (i.e. phaco to remove the cataract and insert an intraocular lens and vitrectomy to repair the retinal detachment) is performed routinely throughout the UK to treat people with a idiopathic macular hole. However, it is not the standard procedure for people with phakic, non-highly myopic RRD.

Rationale for the Comparator Current standard care in the UK is vitrectomy without concomitant cataract extraction), as shown by data from the BEAVRS database.

Research Hypothesis Combined phacovitrectomy will be preferred by patients because it will provide faster visual recovery and obviate the need for a second surgery (the cataract surgery) following RRD repair, and possibly reduce the number of reoperations related to failure to re-attach the retina. Phacovitrectomy may also reduce other health inequalities because if cataract surgery is required after RRD repair, long waiting times for this surgery in the NHS could adversely affect people with lower income who may be unable to achieve visual rehabilitation as quickly as those with higher income who can afford to have their cataracts removed privately.

Research Question In people with non-highly myopic phakic RRD (Population) in whom vitrectomy is planned to repair their RRD, is phacovitrectomy (Intervention) equivalent (equivalence margin +/- 7 ETDRS letters) to vitrectomy and subsequent cataract surgery (phacoemulsification) if/when needed (Comparator) for improving vision following surgery (primary Outcome) but superior for other outcomes in the 52 weeks (+/- 6 weeks) after surgery.

Study aim To conduct a pragmatic randomised trial evaluating clinical and cost-effectiveness, safety and acceptability and patient experience of combined phacovitrectomy vs vitrectomy and subsequent cataract surgery (if/when needed) for non-highly myopic phakic RRD and to undertake a structured analysis of strategies to implement the phacovitrectomy pathway, if this is shown to be as good or better than current standard care.

Study Objectives In people presenting with a phakic, non-highly myopic RRD, the objectives of the COMBAT study are To determine if the clinical effectiveness of phacovitrectomy is equivalent (or superior) to vitrectomy and subsequent cataract surgery (if/when needed).

To compare the cost-effectiveness of phacovitrectomy vs vitrectomy and subsequent cataract surgery (if/when needed).

To evaluate the participant experience and acceptability of phacovitrectomy compared with vitrectomy and subsequent cataract surgery (if/when needed).

To evaluate the post-trial implementation and scalability of phacovitrectomy.

Study Design Pragmatic, allocation-concealed, single-masked (outcome assessors), multicentre, randomised, equivalence trial with an internal pilot to assess feasibility of recruitment.

Internal Pilot The internal pilot will take place during the first nine months of recruitment, to assess feasibility of recruitment and determine if the study should continue to a full trial. The progression criteria will be assessed nine months after the first site is open to recruitment. The target recruitment will be an average of 0.5 participants per month per open site. With staggered opening of sites, the recruitment target for the pilot is 63 participants (23% of the required sample size for the full trial). Criteria for progression to the full trial are GREEN (Average recruitment rate/site/month: 0.5; number of sites opened: 24; number of participants recruited: 63): Progress to full trial.

AMBER (0.25-0.49; 12-23; 31-62): Discuss feasibility with the TSC and NIHR and develop a recovery plan to reach the recruitment target, including evaluating options to improve recruitment and considering number of eligible patients identified, percentage of these patients randomised and reasons for non-randomisation, site recruitment performance, and recruitment procedures.

RED (\<0.25; \<12; \<31): Decision to progress will be made by the TSC and NIHR.

Study Setting Recruitment for COMBAT will take place in at least 30 hospital eye services (HES) across the four UK nations, with catchment areas that cover diverse populations.

Sequence Generation When a potentially eligible person with a RRD is identified, they will be informed about COMBAT. If they are willing to take part, informed consent will be obtained, and eligibility confirmed. If eligible, the baseline visit will be undertaken (as soon as possible and before the surgery) and participants will be randomised (1:1) to receive phacovitrectomy or vitrectomy. An automated system with the allocation concealed to the ophthalmologist recruiting the participant will be used to generate the random allocation sequence. Minimisation will be used to balance allocation across treatment groups for potentially important factors including centre, surgeon's experience (consultant/vitreoretinal fellow), presenting BCVA (BCVA ≥ 69 ETDRS letters \[Snellen equivalent ≥ 20/40; logMAR ≥ 0.3\], 24-68 ETDRS letters \[Snellen equivalent ≤20/50-20/320; logMAR 0.4-1.2\], \<24 ETDRS letters \[Snellen equivalent \<20/320\]); macular status (macula on \& fovea on, macula off \& fovea on, fovea off \<7 days, fovea off 7-14 days, fovea off 15-30 days, fovea off \>30 days); and presence/absence of PVR-C.

Allocation Concealment An automated system will be used to generate the random allocation sequence. This will conceal the allocation from the ophthalmologist.

Allocation Implementation Each p

• Primary anatomical success [Срок оценки: 52 weeks (+/- 6 weeks) after surgery]
• Final anatomical success [Срок оценки: 52 weeks (+/- 6 weeks) after surgery]
• Intraoperative complications [Срок оценки: By 52 weeks (+/- 6 weeks) after surgery]
• Postoperative complications [Срок оценки: By 52 weeks (+/- 6 weeks) after surgery]
• Surgery [Срок оценки: By 52 weeks (+/- 6 weeks) after surgery]
• Refractive error [Срок оценки: 12 weeks after surgery in the phaco-vitrectomy arm and 6-8 weeks post-cataract surgery, if this takes place, as per standard of care, in the vitrectomy only arm]
• BCVA <69 letters [Срок оценки: 52 weeks (+/- 6 weeks) after surgery]
• BCVA <34 letters [Срок оценки: 52 weeks (+/- 6 weeks) after surgery]
• 'Best vision' [Срок оценки: By 52 weeks (+/- 6 weeks) after surgery]
• BCVA from baseline over time [Срок оценки: By 52 weeks (+/- 6 weeks) after surgery]
• Health related quality of life [Срок оценки: 52 weeks (+/- 6 weeks) after surgery]
• Vision-specific quality of life [Срок оценки: 52 weeks (+/- 6 weeks) after surgery]