Patient acceptability of intravitreal complement inhibitors in geographic atrophy (GA): protocol for a UK-based cross-sectional study

Background and rationale

Age-related macular degeneration (AMD) is the most common cause of sight loss in the developed world.1 In the UK, geographic atrophy (GA) is estimated to account for 26% of legal blindness, and globally, approximately 5 million people have GA in at least one eye.2

Patients with GA generally develop regions where the cells die in the retina. Loss of vision due to GA is irreversible, and about half of patients develop GA in both eyes within 7 years of initial diagnosis.3

Regular intravitreal injections (injections into the eye) are the standard of care for wet AMD and a common mode of delivery in the current pipeline of treatments for GA in clinical trials. Dysregulation of the complement cascade has been implicated in the pathogenesis of GA, and recent positive results from phase 3 clinical trials of two intravitreal complement inhibitors have paved a way for new therapies to treat GA.4

Findings from the DERBY and OAKS trials of pegcetacoplan have shown that at 24 months, GA lesion growth was reduced by 21% with monthly intravitreal injections and 17% with every-other-monthly injections.5 6 In the GATHER2 phase 3 trial of avacincaptad pegol, monthly intravitreal injections significantly reduced the mean rate of GA growth over 12 months by 14.3%.7 Indeed, in February 2023, the first-ever treatment for GA, pegcetacoplan (brand name Syfovre), was approved for use by the Food and Drug Administration (FDA) in the USA, based on reduced rates of lesion growth in the DERBY and OAKS trials.8 In August 2023, avacincaptad pegol (brand name Izervay) was approved by the US FDA for clinical use, on the basis of reduced rates of GA growth in the GATHER1 and GATHER2 clinical trials.9 10 Despite these promising developments, the patient perspective on these treatments—specifically whether they perceive the anticipated benefits of these treatments to outweigh the potential burdens and risks of treatment—is unknown.

Acceptability has become a key consideration in the design, evaluation and implementation of healthcare interventions.11 If an intervention is considered acceptable, patients are more likely to adhere to treatment recommendations and to benefit from improved clinical outcomes. While intravitreal therapies are now a mainstay of ophthalmology practice with over 400 000 intravitreal injections delivered annually in the UK alone, the current indications for treatment such as wet AMD, diabetic macular oedema and retinal vein occlusions are very different to GA. Despite evidence of patients receiving intravitreal injections for wet AMD experiencing anxiety, stress and fear of burdening relatives and carers,12–14 the vast majority of wet AMD patients are highly motivated to attend these appointments.15 Indeed, the prevalence of sight loss due to wet AMD has significantly reduced globally since the introduction of intravitreal injections for treatment.16 17 Factors that have been demonstrated to influence non-adherence and non-persistence to intravitreal injection in wet AMD include lower visual acuity at baseline, worsening visual acuity with treatment, distance to treatment centre and high frequency of injections.18 19

In contrast to wet AMD, where a loss of vision is typically sudden and treatment leads to improvements in vision, disease progression and vision loss in GA are a gradual process. In addition, there is significant heterogeneity in the progression of GA and a lack of consensus on methods to accurately predict GA lesion trajectory.20 21 Moreover, proposed treatments for GA may slow down vision loss but will not improve vision.5 7 There is a lack of detailed understanding of the structure-function relationship in GA in order to understand structural changes that actually have an impact on a patient’s visual function and to monitor disease and determine the benefit of any intervention on the disease process.22

It is not yet known whether patients with GA will be similarly motivated to adhere to frequent intravitreal treatments, how often they would be willing to undergo them and what factors would make such treatments acceptable to patients with GA.

We recently conducted a pilot mixed-methods qualitative cross-sectional study with 30 individuals diagnosed with GA to understand the impact these new therapies may have from a patient’s perspective.23 We sought to identify patient-related factors, contexts and circumstances that influence acceptability. Approximately 60% of the cohort found regular intravitreal therapy for GA acceptable while recognising potential burdens and inconveniences. The key underpinning motivation for treatment for people with GA, which emerged in our study, is the high priority placed on continuation with vision-specific activities, particularly for those in worse self-reported health. The factors limiting acceptability were largely clustered around concerns about the magnitude of treatment efficacy, fear of wet AMD and side effects (and, to a lesser extent, the injection procedure itself) and logistics of regular eye clinic visits for treatment. Importantly, we noted a large rise in acceptability when injections were offered every other month compared with monthly. As every-other-monthly injections are associated with an approximately 50% reduction in increased incidence of wet AMD in the phase 3 trials,24 this dosing regimen seems to address two of the three main factors found to limit acceptability in our pilot study. Less frequent injections may also reduce the cumulative risks of procedure-related adverse events, such as endophthalmitis.

Patient-centred care involves patients being active members and shared decision-makers in their own healthcare.25 This necessitates patients being empowered with evidence-based information tailored to them and being supported to evaluate the potential impact of these healthcare decisions. In England, the National Institute for Health and Care Excellence (NICE) works to centrally incorporate shared decision-making into the delivery of information about care and treatment, supported by patient decision aids.26

The current study seeks to confirm the factors that influence patient acceptability of intravitreal complement inhibitor therapies for GA in a larger, more generalisable UK cohort. We will seek to confirm the demographic factors and treatment attributes that influence patient acceptability using a quantitative questionnaire based on the theoretical framework of acceptability (TFA)11 and insights gained from our pilot study and expert input. We hypothesise that patients with GA with lower best-corrected visual acuity (BCVA) in their better-seeing eye would be more likely to find the current regular intravitreal therapies in late-stage development acceptable and that reduction in the frequency of injections would correlate with higher acceptability. The correlations between acceptability, patient demographics and functional and structural biomarkers of GA will also be examined. We anticipate that our results will influence future drug development, creation of shared decision-making tools (such as those developed by National Health Service (NHS) England27) and service design and delivery in the event these treatments are approved for use in clinics. Specifically, this study will tell us more about the specific features around intravitreal treatments that patients with GA find unacceptable, which could then be addressed at the drug development stage or mitigated during the service delivery stage if the treatments are approved in the UK.

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