LEAVO: A Multicentre Phase III Double-masked Randomised Controlled Non-Inferiority Trial comparing the clinical and cost effectiveness of intravitreal therapy with ranibizumab (Lucentis) vs aflibercept (Eylea) vs bevacizumab (Avastin) for Macular Oedema (MO) due to Central Retinal Vein Occlusion (CRVO)

Hasan Basarir; P Hykin; S Sivaprasad; AT Prevost; J Vasconcelos; Caroline Murphy; J Kelly; J E Brazier; Hasan Basarir; Simon Harding; Yit C Yang; Usha Chakravarthy; Andrew Lotery

LEAVO

A Multicentre Phase III Double-masked Randomised Controlled Non-Inferiority Trial comparing the clinical and cost effectiveness of intravitreal therapy with ranibizumab (Lucentis) vs aflibercept (Eylea) vs bevacizumab (Avastin) for Macular Oedema (MO) due to Central Retinal Vein Occlusion (CRVO)

Hykin, P., Sivaprasad, S., Prevost, A. T., Vasconcelos, J., Murphy, C., Kelly, J., Brazier, J. E., Basarir, H., Harding, S., Yang, Y. C., Chakravarthy, U., & Lotery, A. (2016). LEAVO: A Multicentre Phase III Double-masked Randomised Controlled Non-Inferiority Trial comparing the clinical and cost effectiveness of intravitreal therapy with ranibizumab (Lucentis) vs aflibercept (Eylea) vs bevacizumab (Avastin) for Macular Oedema (MO) due to Central Retinal Vein Occlusion (CRVO). The Lancet, (Protocol Review 14PRT/06545). http://www.thelancet.com/protocol-reviews/14PRT-06545

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Abstract

(LEAVO trial) ‒ ISRCTN: 13623634

Background

Central retinal vein occlusion with macular oedema causes visual impairment untreated. Despite evidence for the clinical effectiveness of the intravitreal anti-VEGF drugs ranibizumab, aflibercept and bevacizumab, there has been no clinical trial to compare them.

Aim

To compare the relative clinical and cost effectiveness of bevacizumab (investigational treatment), aflibercept (investigational treatment) and ranibizumab (standard care) in macular oedema due to central retinal vein occlusion over 100 weeks.

Methods

Study design

This is multicentre, phase III, double masked randomised controlled non-inferiority trial.

Inclusion and exclusion criteria

We will include patients of either sex, aged at least 18 years with macular oedema due to central retinal vein occlusion of no more than 12 months duration, study eye best corrected visual acuity (BCVA) at least 19 and 78 Early Treatment Diabetic Retinopathy Study (ETDRS) letters or fewer (Snellen visual acuity 3/60 to 6/9) and central subfield thickness greater than 320μm on optical coherence tomography. The main exclusion criteria are co-existent ocular conditions affecting BCVA and diabetic retinopathy.

Method of Randomisation

459 patients will be individually randomly assigned with minimisation to stratify for visual acuity, central retinal vein occlusion duration and whether previously treatment naïve.

Interventions

Intravitreal bevacizumab (1.25mg/μL], aflibercept (2.0mg/50μL) and ranibizumab (0.5mg/50μL) given by four mandated injections at baseline, 4, 8, and 12 weeks, followed by therapy every 4 to 8 weeks if pre-specified re-treatment criteria are met and visual acuity of 83 ETDRS letters or fewer at all visits until week 96.

Primary and secondary outcomes

The primary outcome is change in BCVA from baseline to 100 weeks in the study eye of all patients measured by ETDRS letter score at 4 metres. Secondary outcomes are ≥ 15, ≥ 10, <15, and ≥ 30 letter change, optical coherence tomography central subfield thickness and macular volume, from baseline to 52 and 100 weeks, quality of life and resource utilisation scales at 0,12, 24, 52, 76 and 100 weeks, and local and systemic safety profiles.

Power calculation

130 patients analysed per group provides 80% power to reject the null hypotheses that bevacizumab and aflibercept are inferior to ranibizumab, at the 5% significance level provided the estimated difference in primary outcome is above the five-letter non inferiority margin, assuming a standard deviation of 14.3 and allowing for 15% missing data.

Analysis plan

Per-protocol and intention-to-treat analyses are required to establish non-inferiority, and all other analyses will be intention-to-treat, except for adverse effects, anatomical outcomes and injection number that will be summarised. Mean costs and quality-adjusted life-years (QALYs) will be calculated, cost-utility analysis done and incremental cost per QALY gained calculated.

Funder

National Institute for Health Research Health Technology Assessment Programme (11/92/03) and supported by NIHR Moorfields Biomedical Research Centre, London, UK.

Start date

Dec 12, 2014.

Expected end date

Aug 31, 2018.

Expected submission date

January, 2019.