YOSEMITE and RHINE: Phase 3 Randomized Clinical Trials of Faricimab for Diabetic Macular Edema: Study Design and Rationale.

Nicole Eter,Karen Basu,Jeffrey R Willis,David Silverman,Rishi P Singh,Francis Abreu,Paisan Ruamviboonsuk,Charles C Wykoff,Zdenka Haskova,Andrew Chang,Hugh Lin,Kemal Asik,Karl G Csaky,Carlos Quezada Ruiz,Caroline Baumal

doi:10.1016/j.xops.2021.100111

Abstract

PurposeFaricimab is a novel anti–angiopoietin-2 and anti–vascular endothelial growth factor (VEGF) bispecific antibody with high affinities and specificities for both VEGF and angiopoietin-2. It is postulated that targeting angiogenic factors and inflammatory pathways in addition to the VEGF pathway will increase treatment durability and improve outcomes. The phase 3 YOSEMITE (ClinicalTrials.gov identifier, NCT03622580) and RHINE (ClinicalTrials.gov identifier, NCT03622593) trials are designed to assess efficacy, safety, and durability of faricimab compared with aflibercept in patients with diabetic macular edema (DME). The trials evaluate a personalized treatment interval (PTI) approach to address heterogeneity in treatment response among patients with DME.DesignTwo identically designed, global, double-masked, randomized, controlled phase 3 trials (YOSEMITE and RHINE).ParticipantsAdults with center-involving DME secondary to type 1 or 2 diabetes mellitus.MethodsThese studies were designed to evaluate 3 treatment groups: faricimab 6.0 mg dosed either at fixed dosing every 8 weeks after initial treatment with 6 intravitreal doses at 4-week intervals, or faricimab 6.0 mg dosed according to PTI after initial treatment with 4 every-4-week doses, compared with aflibercept 2.0 mg dosed every 8 weeks after 5 initial every-4-week doses. The primary end point of the studies was change from baseline in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Secondary end points included anatomic, durability, and patient-reported outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. The PTI is a protocol-defined flexible regimen based on the treat-and-extend concept, which allowed up to every-16-week adjustable dosing based on objective and standardized criteria. The PTI design aimed to maximize therapeutic results while minimizing treatment burden.Main Outcome MeasuresWe describe the rationale for the study design and the novel PTI (up to every-16-week adjustable dosing) approach for treatment with faricimab.ResultsYOSEMITE and RHINE enrolled 940 and 951 patients, respectively. Results from each study will be reported separately.ConclusionsYOSEMITE and RHINE were the first registrational trials in retinal disease to incorporate an objective PTI regimen, allowing for up to every-16-week adjustable dosing with a dual angiopoietin-2 and VEGF-A inhibitor, faricimab 6.0 mg, for treatment of DME.

Highlights

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record
-p ro of for the phase 3 studies of faricimab in DME, to eliminate bias, and to ensure robust and reproducible results, we aimed to develop a personalized treatment interval (PTI) regimen based on T&E methodology
The phase 3 YOSEMITE and RHINE trials for DME were designed to primarily show noninferiority of faricimab compared with aflibercept in the ITT population, which included both anti-VEGF treatmentnaïve and previously treated patients

Summary

Introduction

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. YOSEMITE and RHINE: Phase 3 Randomized Clinical Trials of Faricimab for Diabetic Macular Edema: Study Design and Rationale

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