Title: Clinical Efficacy and Mechanistic Evaluation of Aflibercept for Proliferative Diabetic Retinopathy (acronym CLARITY)
Funder: Department of Health (England)

Abstract: HYPOTHESIS: It is hypothesised that 1. inhibition of VEGF by aflibercept causes regression of retinal neovascularisation and may limit retinal non-perfusion thereby retarding progression of diabetic retinopathy and 2. proliferative diabetic retinopathy (PDR) can be successfully managed in clinical practice with aflibercept rather than conventional panretinal photocoagulation (PRP) by inhibition of retinal derived VEGF responsible for retinal neovascularisation bleeding and scarring. AIMS: 1. To explore by mechanistic evaluation whether repeated intravitreal aflibercept compared to PRP retards the progression of PDR reducing quantifiable areas of retinal non-perfusion improving intravascular retinal oxygen saturation and causing regression of retinal neovascularisation 2. To explore the clinical efficacy safety profile and cost-effectiveness of repeated intravitreal aflibercept compared to PRP in treating PDR in a phase 2 randomised active-controlled clinical trial. DESIGN: Mechanistic evaluation: this is a single-centre two-arm prospective parallel group active-controlled single-masked exploratory analyses embedded within the initial phase of the efficacy study randomized 1:1 to repeated intravitreal aflibercept versus conventional PRP in 40 participants with PDR. Outcomes will be measured at 12 months. Main Efficacy Clinical Trial: this is a multicentre two-arm prospective parallel group active-controlled single-masked randomiszed controlled clinical trial of intravitreal aflibercept versus conventional PRP in 220 participants with PDR including those in the mechanistic evaluation. Primary and secondary outcomes will be assessed at 12 months. POPULATION: Adults (18+ years) with type 1 or 2 diabetes mellitus and treatment naïve or previously laser-treated but persistent PDR. PLANNED INTERVENTIONS: Intravitreal aflibercept 2 mg at week 0 1 and 2 months with reassessment at month 3 and participants will continue on as required aflibercept dependent on the regression of retinal neovascularisation. If recurrent retinal neovascularisation occurs in any arm monthly aflibercept will be re-started until total regression. CONTROL TREATMENT: PRP in 2 sessions 2 weeks apart in treatment naïve patients and 1 session in persistent retinal neovascularisation with the option of more laser therapy as required. OUTCOMES: Mechanistic evaluation at 12 months i) Areas of retinal non-perfusion on fluorescein angiography; ii) Retinal intravascular oxygen saturation iii)Area of retinal neovascularisation. Main Efficacy Clinical Trial Primary outcome: Difference between arms in best corrected visual acuity letter score (BCVA) at 12 months. Secondary outcomes at month 12 will include differences between arms in i) driving visual fields ii) contrast sensitivity iii) vision related quality of life outcomes iv) treatment response questionnaire outcomes v) area of retinal neovascularisation vi) area of capillary non-perfusion vii) OCT central macular thickness ix) requirement for vitrectomy x)Safety outcomes: adverse event rate xi) cost-effectiveness. ASSESSMENTS: Participants in the clinical efficacy study including those in the embedded mechanistic evaluation will undergo best corrected visual acuity (BCVA) contrast sensitivity driving visual field testing vision related treatment statisfaction and economic analysis questionnaires colour fundus photography OCT and fundus fluorescein angiography at baseline and month 12. At intervening monthly time points open aperture BCVA clinical examination OCT and colour fundus photography will be performed. SAMPLE SIZE: The mechanistic study is an exploratory study clinical study sample size calculations were performed using nQuery Advisor 4.0 software. With 110 patients randomised per arm (total 220) 188 will be followed (15% dropout) for 12 months providing 90% power to detect a clinically relevant mean difference of 5 letters in the 12 month BCVA ETDRS score between Aflibercept and laser arms adjusting for baseline score and a 5% level of significance based on a standard deviation of 10.3. STATISTICAL ANALYSIS: Analyses will primarily be on an intention to treat basis. Although a low rate of missing data is anticipated a sensitivity analysis will be undertaken using baseline and available reported measurements of the primary outcome using a linear mixed effects model with full polynomial terms over time by arm. This will provide an estimate of the treatment difference at the 12-month time-point under a missing at random assumption. Analyses of secondary outcomes will be reported as differences in means or proportions for continuous and binary data respectively. All tests will be two-sided and at the 12-month primary time-point will be assessed at the 5% significance level. Safety outcomes will be reported as patient proportions and rates within and between arms using exact methods where appropriate. ECONOMIC BENEFIT: The incremental cost-effectiveness of intravitreal aflibercept versus conventional PRP treatment at 12 months will be compared. DURATION OF STUDY AND EXPECTED RECRUITMENT RATE: 36 months as follows: Preparation (study months -4 to 2); Recruitment: Month 3-15; Assessments: up to Month 27; Analyses: 28-36 months. We expect the study to start within 6 months of funding. 220 patients will be recruited over 12 months. Each centre will recruit 22 subjects in a year i.e. 1-3 a month for full recruitment by 12 months. JUSTIFICATION OF ESTIMATE: Research funding: CTU: web based randomisation programme and host trial data entry system IMP supply to site pharmacies data manager to clean data and report quality and compliance ensure trial manager works to CTU SOPs statistical support research fellow and consumables costs for mechanistic evaluation health economics Reading centre and Image analyses expertise. NHS support costs and excess treatment costs: nurse support for identification and recruitment.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: EYE;METABOLIC AND ENDOCRINE