Elsevier

The Lancet

Volume 389, Issue 10085, 3–9 June 2017, Pages 2193-2203
The Lancet

Articles
Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): a multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial

https://doi.org/10.1016/S0140-6736(17)31193-5Get rights and content

Summary

Background

Proliferative diabetic retinopathy is the most common cause of severe sight impairment in people with diabetes. Proliferative diabetic retinopathy has been managed by panretinal laser photocoagulation (PRP) for the past 40 years. We report the 1 year safety and efficacy of intravitreal aflibercept.

Methods

In this phase 2b, single-blind, non-inferiority trial (CLARITY), adults (aged ≥18 years) with type 1 or 2 diabetes and previously untreated or post-laser treated active proliferative diabetic retinopathy were recruited from 22 UK ophthalmic centres. Patients were randomly assigned (1:1) to repeated intravitreal aflibercept (2 mg/0·05 mL at baseline, 4 weeks, and 8 weeks, and from week 12 patients were reviewed every 4 weeks and aflibercept injections were given as needed) or PRP standard care (single spot or mutlispot laser at baseline, fractionated fortnightly thereafter, and from week 12 patients were assessed every 8 weeks and treated with PRP as needed) for 52 weeks. Randomisation was by minimisation with a web-based computer generated system. Primary outcome assessors were masked optometrists. The treating ophthalmologists and participants were not masked. The primary outcome was defined as a change in best-corrected visual acuity at 52 weeks with a linear mixed-effect model that estimated adjusted treatment effects at both 12 weeks and 52 weeks, having excluded fluctuations in best corrected visual acuity owing to vitreous haemorrhage. This modified intention-to-treat analysis was reapplied to the per protocol participants. The non-inferiority margin was prespecified as −5 Early Treatment Diabetic Retinopathy Study letters. Safety was assessed in all participants. This trial is registered with ISRCTN registry, number 32207582.

Findings

We recruited 232 participants (116 per group) between Aug 22, 2014 and Nov 30, 2015. 221 participants (112 in aflibercept group, 109 in PRP group) contributed to the modified intention-to-treat model, and 210 participants (104 in aflibercept group and 106 in PRP group) within per protocol. Aflibercept was non-inferior and superior to PRP in both the modified intention-to-treat population (mean best corrected visual acuity difference 3·9 letters [95% CI 2·3–5·6], p<0·0001) and the per-protocol population (4·0 letters [2·4–5·7], p<0·0001). There were no safety concerns. The 95% CI adjusted difference between groups was more than the prespecified acceptable margin of −5 letters at both 12 weeks and 52 weeks.

Interpretation

Patients with proliferative diabetic retinopathy who were treated with intravitreal aflibercept had an improved outcome at 1 year compared with those treated with PRP standard care.

Funding

The Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership.

Introduction

Proliferative diabetic retinopathy (PDR) is the commonest cause of severe visual loss in people with diabetes.1 This condition is characterised by the growth of new abnormal vessels on the retina or optic disc that can result in sight threatening complications such as vitreous haemorrhage and tractional retinal detachment.

Panretinal laser photocoagulation (PRP) has been the standard of care for this condition for more than 40 years and reduces the risk of severe visual loss by 50%.2 Patients identified with active PDR are treated urgently to complete initial PRP and then reviewed regularly to identify and treat recurrent or de novo active neovascularisation with supplemental PRP. Repeated supplemental PRP is associated with permanent sequelae on visual function including final visual acuity below the driving standard, restricted visual fields that preclude driving, night vision difficulties, loss of colour vision and reduced contrast sensitivity, and increased macular oedema.3, 4, 5, 6, 7 Although laser technology and techniques have evolved over the past decade to reduce side-effects,5, 6 approximately 4·5% progress to require vitrectomy surgery.8 Therefore, there is a substantial unmet need for novel treatments that reduce the risk of severe visual loss in PDR that is non-inferior to PRP with fewer side-effects.

Research in context

Evidence before this study

Panretinal laser photocoagulation (PRP) is the standard of care for patients with proliferative diabetic retinopathy. Presently, three anti-vascular endothelial growth factor (anti-VEGF) therapeutic agents are administered by intravitreal injections to treat ophthalmic conditions. Bevacizumab and ranibizumab are monoclonal antibodies against VEGF-A. Before this trial, we reviewed PubMed articles published between Jan 1, 2005, and Jan 31, 2014, and there were eight short-term (3–6 months), randomised controlled trials comparing either bevacizumab or ranibizumab monotherapy or in combination with PRP versus PRP alone in high-risk patients with proliferative diabetic retinopathy. These randomised controlled trials showed new vessel regression with these biological agents within 3–4 months. Aflibercept is the latest anti-VEGF agent and it blocks all isomers of VEGF-A, VEGF-B, placental growth factor 1, placental growth factor 2, and galectin-1. To date, there have been no randomised controlled trials of aflibercept in patients with proliferative diabetic retinopathy.

We updated the literature review on March 1, 2017. A well designed multicentre clinical trial comparing ranibizumab monotherapy versus PRP in patients with high-risk proliferative diabetic retinopathy, with and without macular oedema, has been published. The primary outcome of this randomised controlled trial at 2 years showed non-inferiority of ranibizumab versus PRP in patients at a high risk of proliferative diabetic retinopathy with a median of ten injections over 2 years (seven injections in the first year). However, this trial has not changed clinical practice worldwide due to the perceived practical difficulties of delivering repeated intravitreal injections in patients with proliferative diabetic retinopathy. Additionally, the study only showed non-inferiority of best corrected visual acuity to PRP, albeit with beneficial secondary outcomes. Therefore, PRP remains the preferred choice. Additionally, a substantial proportion of patients after initial PRP are under long-term follow-up in retinal clinics to identify and treat reactivation of existing neovascularisation with supplemental PRP and these patients have been excluded from previous clinical trials. Therefore, the role of anti-VEGF in this patient cohort remains unclear.

Added value of this study

The CLARITY study is the first randomised controlled trial, to our knowledge, of intravitreal aflibercept in proliferative diabetic retinopathy and the results provide substantial evidence that the visual outcome of active proliferative diabetic retinopathy at 1 year with aflibercept therapy is superior to PRP. This study is also the first to show a superior visual acuity outcome with an anti-VEGF agent in eyes with proliferative diabetic retinpathy with no baseline macular oedema compared with PRP therapy. Furthermore, this effect was achieved with four aflibercept injections (a median of one injection after the three loading doses in a year) irrespective of the proliferative diabetic retinopathy risk status and previous PRP treatment history, providing important evidence that aflibercept therapy can be adopted as an alternative to PRP in the first year of therapy. The study also showed a significantly lower incidence of macular oedema and vitreous haemorrhage and fewer adverse effects on binocular visual acuity and visual fields with aflibercept compared with PRP, further highlighting the advantages of aflibercept over PRP with similar systemic adverse effects. Most importantly, the patient satisfaction scores suggest a patient preference for aflibercept therapy over PRP in a clinical trial setting.

Implications of all the available evidence

In the first year of therapy, aflibercept is an effective treatment for active proliferative diabetic retinopathy and might be adopted as an alternative option to PRP.

Ranibizumab and bevacizumab, monoclonal antibody inhibitors of vascular endothelial growth factor A (VEGF-A), have been shown to cause short-term new vessel regression, either as monotherapy or in combination with PRP.9 Since this study commenced, a randomised clinical trial comparing ranibizumab and PRP reported 2 year outcomes in high-risk PDR with and without macular oedema and showed ranibizumab monotherapy is non-inferior to PRP, with less visual field loss and incident vitrectomy.10 The latest anti-VEGF agent, aflibercept, is a recombinant fusion protein comprising the binding domains of VEGF-1 and VEGF-2 receptors, binds to VEGF with a greater affinity than ranibizumab or bevacizumab, and shows activity against VEGF-A, VEGF-B, and placental growth factor.11 This study is the first, to our knowledge, to assess efficacy and safety of intravitreal aflibercept in the management of PDR.

Section snippets

Study design and participants

CLARITY is a multicentre, prospective, two-arm, parallel-group, single-blind, randomised, controlled, phase 2b, non-inferiority trial. Patients were recruited from 22 UK National Health Service hospitals.

The study was granted approval by the National Research Ethics Committee Service London, South East (14/LO/0203). Clinical Trials Authorisation was given by the Medicines and Healthcare Products Regulatory Agency (11518/0013/001–0001) and the European Union Drug Regulating Authorities Clinical

Results

Between Aug 22, 2014 and Nov 30, 2015, 290 patients were assessed for eligibility and 232 were randomly assigned to receive intravitreal aflibercept (n=116) or PRP (n=116; figure 1).

Baseline characteristics were well balanced between treatment groups (table 1). Of 232 patients, a total of 123 (53%) previously untreated patients and 109 (47%) previously treated patients were recruited. Mean best corrected visual acuity at baseline was 81·4 ETDRS letters (SD 8·1). At baseline of 232 patients, 21

Discussion

The results of this phase 2b trial show that intravitreal aflibercept monotherapy is non-inferior and superior to standard PRP treatment for PDR through 52 weeks. This study is the first, to our knowledge, to show that an anti-VEGF therapy can provide superior best corrected visual acuity outcomes in eyes with active PDR without baseline centre-involving macular oedema. Mean differences in best corrected visual acuity letter score between groups in favour of aflibercept was small but

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