Anti-vascular Endothelial Growth Factor (Anti-VEGF) Monotherapy vs Anti-VEGF Followed by Subthreshold Micropulse Laser for Treating Severe Diabetic Macular Oedema When the Central Retina Goes <400 Microns

Background DMO is a leading cause of sight loss in people living with diabetes (PLWD). Considering the prevalence of DMO (7%) and diabetes (\~4.8 million), around 336,000 PLWD have DMO in the UK. With its increasing incidence, DMO will continue to be a burden to society. In DMO, fluid collects at the macula, the area that gives central vision, leading to sight loss. As fluid accumulates, the macula thickens. This is measured in microns (μm) with optical coherence tomography (OCT) scans. A measure of central retinal subfield thickness (CRT) is obtained with OCT scans when DMO is diagnosed, guiding treatment selection. National Institute for Health and Care Excellence (NICE) guidance advises intraocular injections of anti-VEGF for PLWD presenting with severe (CRT ≥400μm) centre involved DMO. For PLWD presenting with milder forms of centre involved DMO (CRT \<400μm), NICE advises macular laser because it is as effective as anti-VEGFs but costs less.

Most patients presenting to UK Hospital Eye Services (HES) have DMO with CRT ≥400μm and are treated with anti-VEGFs. Currently, as per standard practice, anti-VEGFs are given monthly initially (loading dose) and then typically every 1-3 months until the macula dries, even if CRT falls to below 400μm. In 72% of people on anti-VEGFs, the fluid remains until at least the second year of treatment. Trials have shown that after 5 years, 38-48% of participants still require anti-VEGFs either because DMO remains or because it recurs after clearing once anti-VEGFs are stopped. Most patients on anti-VEGFs need follow-up for life. Anti-VEGFs are expensive and carry potential harms including increased intraocular pressure, retinal detachment, cataract, and infection (endophthalmitis). The latter, although rare, can lead to total blindness. Furthermore, intraocular injections cause discomfort to many patients during administration and for hours thereafter and elicit anticipatory stress responses. Research has shown that a significant proportion of patients (25%) experience high levels of preprocedural anxiety, and nearly 10% report high levels of pain. Other experiences of treatment burden, not commonly assessed in previous studies, have been found to be important including time and functional disruption associated with intravitreal injections. Moreover, HES are unable to cope with the demand and injections are not being given in a timely manner, which has a negative impact on outcomes and the cost-effectiveness of the treatment. Finding ways to reduce the number of injections to optimise patient experience and maximise adherence is a goal pursued worldwide.

Trials comparing anti-VEGFs with standard macular laser have shown superior efficacy of anti-VEGFs against laser in severe DMO. These trials included predominantly eyes with very thickened retinas (e.g. \>460μm in RISE and RIDE and \>479μm in VIVID and VISTA. When anti-VEGFs were used in combination with macular laser in some of these trials, combined treatment (anti-VEGFs and macular laser) did not appear to be superior to anti-VEGFs alone. However, macular laser was not necessarily applied when CRT had gone below 400μm following anti-VEGFs. It would be at this stage that macular laser would have more chance to be effective, as its penetration through the neurosensory retina and areas of macular oedema, and subsequently, its uptake by the retinal pigment epithelium (RPE) would be more adequate when compared with its likely reduced penetration and effect on the RPE when the macula is very thickened by marked DMO.

Rationale DAME will be a pragmatic trial comparing clinical- and cost-effectiveness, side effects and participant experience and acceptability of combined treatment with anti-VEGFs + Subthreshold Macular Laser (SML) for participants who present with severe DMO and are treated initially with anti-VEGF, with the SML applied after CRT falls to \<400μm (when laser has more chance to succeed), versus the current standard of care of continuing with anti-VEGF monotherapy even when the CRT falls below 400μm if DMO is present.

DAME follows from the DIAMONDS trial, which showed that SML, which does not damage the macula, is as effective to treat DMO of \<400μm as standard laser, which produces a burn. Although DIAMONDS participants had poor glycaemic control (mean HbA1c 8.5%), most maintained excellent sight and fulfilled driving standards throughout their 2-year follow-up. Those treated with SML needed, on average, only two sessions of laser, with clinic visits every 3-4 months and only 18% received rescue treatment with anti-VEGFs, with an average total cost of care of £898 per participant (similar to the cost of the drug in a single anti-VEGF injection).

The hypothesis for DAME is that treating people with severe DMO (CRT ≥400μm) initially with anti-VEGFs and then, when CRT goes below 400μm, continuing with SML every 2-3 months until DMO clears will be as effective but more cost-effective, have fewer side effects and be preferred by people with DMO when compared to continuing with anti-VEGF monotherapy. If SML allows people initially treated with anti-VEGFs to maintain the characteristic early vision gains that are observed following the first few anti-VEGF injections this new strategy could become the new standard of care for people with severe DMO and be implemented worldwide. Potential benefits would include fewer injections with subsequent reduction in inconvenience, stress, harms and costs, and fewer clinic visits, which will facilitate patient's compliance with the treatment and reduce costs and inconvenience to people with severe DMO.

A Cochrane network meta-analysis found that anti-VEGFs improve vision in DMO but concluded "evidence from RCTs may not apply to real-world practice where people are often undertreated and under-monitored". In this regard, a large cohort study from Moorfields Eye Hospital found that half of the patients with DMO treated with anti-VEGFs achieved vision of 70 ETDRS letters at 1.9 months of initiating this therapy but, in 50% of these, vision dropped below this by 14.7 months (i.e. visual gain was not maintained). Similarly, a "real world" analysis of 28,658 eyes of participants with DMO treated with anti-VEGFs found that eyes with good vision at baseline (before initiating anti-VEGF therapy), were at risk of visual loss a year following treatment initiation, highlighting that outcomes observed in anti-VEGF trials are not reproduced in clinical practice.

Rationale for the Intervention Macular laser is likely to be effective in combination with anti-VEGFs in people initially presenting with ≥400μm DMO if the macula laser is applied after the CRT has gone below 400μm following anti-VEGFs. A Single Technology Appraisal by NICE found that for people presenting with DMO and CRT of \<300μm, there was no statistically significant difference in efficacy between anti-VEGFs and laser, but laser was more cost-effective. When CRT was between 300μm and 400μm, there were gains in vision of 7 ETDRS letters with anti-VEGFs and 4 ETDRS letters with macular laser, a statistically significant difference but of doubtful clinical relevance; and macular laser dominated in cost-effectiveness.

A randomised trial by the Diabetic Retinopathy Clinical Research Network (Protocol V) including people presenting with DMO and good vision (median 85 ETDRS letters), with CRT of \<400μm (median 290μm and 299μm in aflibercept and macular laser arms, respectively) and median HbA1c of 7.6% showed comparable efficacy between aflibercept and macular laser, with 16% and 17% of participants experiencing improvement in best corrected visual acuity (BCVA) of \>5 ETDRS letters at 2 years. The DIAMONDS trial showed that macular laser is effective and cost-effective for treating people presenting with DMO and CRT \<400μm. Participants who had good vision (median 82 ETDRS letters), median CRT of 331μm and median HbA1c of 8.5% (i.e. more severe disease than those included in Protocol V) maintained good sight throughout the 2-year follow-up (mean change in vision of less than 3 ETDRS letters) with 18% of participants experiencing an improvement in BCVA of \>5 ETDRS letters at two years.

In clinical practice, macular laser is offered only to people presenting with new DMO with CRT \<400μm but not routinely to those who have started anti-VEGFs, even if, at some point, their CRT is \<400μm. The proposed strategy (initial anti-VEGF therapy for people presenting with severe DMO with CRT of ≥400μm followed by macular laser after CRT goes below 400μm) would likely allow participants to achieve visual acuity improvement (which often occurs following the first few anti-VEGF injections but is less frequently observed after macular laser monotherapy) but without the need to continue with anti-VEGF injections long-term. The DAME PPI Group felt that participants would be likely to prefer this new proposed strategy (anti-VEGF followed by SML).

The DIAMONDS trial in people presenting with DMO of \<400μm showed that SML, which does not produce any deleterious functional or structural changes in the retina, is as effective as standard laser, which produces a burn. A systematic review on SML for DMO identified 5 small (30-56 eyes in total in each trial) randomised trials comparing anti-VEGFs alone with anti-VEGFs + SML. In 4 of these trials, no statistically significant differences in BCVA were found between treatment groups, whereas in one a significant improvement in BCVA was observed only in the combined anti-VEGF+SML group. A statistically significantly reduced number of anti-VEGF injections was required in the anti-VEGF+SML group in 3 of the 4 trials in which this outcome was investigated. None of the trials included other important outcomes such as health-related and visual-related quality of life, participant-reported experience, adverse events, or costs. The CRT in these trials varied (means of 494-513μm, 462-457μm, 458-470μm, 466-451μm, 433-458μm) and the SML was applied after randomisation (i.e. not when CRT had gone below 400μm following anti-VEGFs).

Rationale for the Comparator The comparator in DAME will be the current standard of care for these patients: continuing with anti-VEGF monotherapy until DMO fully clears or if it recurs after having previously dried, based on OCT scans. Sites will use the type of anti-VEGF they routinely use in their standard clinical practice.

Research Hypothesis DAME will test whether, in people presenting with severe DMO (CRT ≥400μm) who are initially treated with anti-VEGFs, treatment with SML (intervention) after their CRT has decreased to \<400μm is equivalent (equivalence margin +/- 5 Early Treatment Diabetic Retinopathy Study \[ETDRS\] letters) to continuing anti-VEGF monotherapy (control, comparator = standard of care) for preserving/improving BCVA in the study eye at 104 weeks (primary outcome).

Aim To conduct a pragmatic randomised equivalence trial to assess clinical- and cost-effectiveness, safety, participant experience and acceptability of SML applied after CRT is \<400μm following initial anti-VEGF injections, compared to continued anti-VEGF monotherapy, in people who originally presented with severe DMO (CRT ≥400μm). DAME includes an assessment of service providers and planners of factors that enable sustainable delivery of the service to participants, assuming a positive trial result, after the study.

Objectives

In people initially presenting with severe DMO (CRT ≥400μm) who receive treatment with anti-VEGFs and once their macular CRT, as determined on OCT scans, has decreased to \<400μm:

1. To determine if the clinical effectiveness of anti-VEGFs and SML is equivalent to anti-VEGF monotherapy 2. To determine the cost-effectiveness of anti-VEGFs and SML compared to anti-VEGF monotherapy 3. To evaluate the participant experience and acceptability of anti-VEGFs and SML compared to antiVEGF monotherapy 4. To evaluate the post-trial implementation

• Central Retinal Thickness (CRT) in the study eye [Time frame: 104 weeks after randomisation]
• Health-related and vision-related quality of life [Time frame: 104 weeks after randomisation]
• Safety of procedures [Time frame: By 104 weeks after randomisation]
• Treatments used in the study eye [Time frame: By 104 weeks after randomisation]
• "Rescue" treatment in the study eye [Time frame: By 104 weeks after randomisation]
• Treatment discontinuation [Time frame: By 104 weeks after randomisation]
• Loss of BCVA [Time frame: 104 weeks after randomisation]
• Gain of BCVA [Time frame: 104 weeks after randomisation]
• CRT ≤300μm [Time frame: 104 weeks after randomisation]
• Diabetic macular oedema (DMO) [Time frame: 104 weeks after randomisation]
• Use of health and social care services (assessed with a study specific questionnaire) [Time frame: Completed at every visit, regardless of whether the participant received treatment or not, up to week 104.]
• Non-healthcare costs to the participants (assessed with a study specific Patient Cost Questionnaire) [Time frame: To be completed by patients at approximately 26 weeks and 78 weeks.]