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

Abstract

Purpose: Faricimab 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.

Design: Two identically designed, global, double-masked, randomized, controlled phase 3 trials (YOSEMITE and RHINE).

Participants: Adults with center-involving DME secondary to type 1 or 2 diabetes mellitus.

Methods: These 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 measures: We describe the rationale for the study design and the novel PTI (up to every-16-week adjustable dosing) approach for treatment with faricimab.

Results: YOSEMITE and RHINE enrolled 940 and 951 patients, respectively. Results from each study will be reported separately.

Conclusions: YOSEMITE 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.

Keywords: AE, adverse event; Adjustable dosing; Angiopoietin-2; Anti–vascular endothelial growth factor; BCVA, best-corrected visual acuity; Bispecific antibody; CFP, color fundus photography; CRC, central reading center; CST, central subfield thickness; DME, diabetic macular edema; DR, diabetic retinopathy; Diabetic macular edema; ETDRS, Early Treatment Diabetic Retinopathy Study; FFA, fundus fluorescein angiography; Faricimab; ITT, intention-to-treat; IxRS, interactive voice or web-based response system; PRN, pro re nata; PTI, personalized treatment interval; Personalized treatment interval; Phase 3 clinical trial design; SD, spectral-domain; T&E, treat-and-extend; VEGF, vascular endothelial growth factor.

© 2021 by the American Academy of Ophthalmology.

Figures

Figure 1

Diagram showing study design overview. ∗The personalized treatment interval (PTI) is a protocol-driven regimen based on the treat-and-extend concept. †Change from baseline in best-corrected visual acuity (BCVA), as measured on the ETDRS chart at a starting distance of 4 m at 1 year, is the average of the week 48, 52, and 56 visits. Q8W = every 8 weeks; R = randomization.

Figure 2

Decision tree for interactive voice or web-based response system–determined personalized treatment interval arm dosing intervals. ∗The first central subfield thickness (CST) value that is †The mean of the 3 best best-corrected visual acuity (BCVA) scores obtained at any previous active dosing visit. Q4W = every 4 weeks; Q16W = every 16 weeks.

Figure 3

Graphs showing personalized treatment interval scenario examples. Horizontal line represents central subfield thickness (CST) threshold of 325 μm. Weeks in boldface indicate when active treatment was administered. A, Central subfield thickness threshold of < 325 μm (represented by solid horizontal line) not met: patient continues every-4-week (Q4W) treatment. B, Week 12: CST < 325 μm, extend to every 8 weeks (Q8W); week 20: CST within ±10% of reference CST∗ (with no associated ≥10-letter best-corrected visual acuity [BCVA] decrease from reference BCVA†), extend to every 12 weeks (Q12W); week 32: within ±10% of reference CST (with no associated ≥10-letter BCVA decrease from reference BCVA), extend to every 16 weeks (Q16W); week 48: CST within ±10% of reference CST (with no associated ≥10-letter BCVA decrease from reference BCVA), maintain at Q16W. C, Week 12: CST < 325 μm, extend to Q8W; week 20: CST within ±10% of reference CST (with no associated ≥10-letter BCVA decrease from reference BCVA), extend to Q12W; week 32: CST within ±10% of reference CST (with no associated ≥10-letter BCVA decrease from reference BCVA), extend to Q16W; week 48: CST increased by more than 10%, but no more than 20% (with an associated ≥5-letter to <10-letter BCVA decrease), reduce to Q12W. D, Week 12: CST < 325 μm, extend to Q8W; week 20: CST within ±10% of reference CST (with no associated ≥10-letter BCVA decrease from reference BCVA), extend to Q12W; week 32: CST within ±10% of reference CST (with no associated ≥10-letter BCVA decrease from reference BCVA), extend to Q16W; week 48: CST increased by more than 10% (with an associated ≥10-letter BCVA decrease from reference), reduce to Q8W. ∗The first CST value that is < 325 μm (defined as the central 1-mm thickness from the internal limiting membrane to Bruch’s membrane), starting at week 12. Reference CST is adjusted if CST decreases by >10% from the previous reference CST for 2 consecutive study drug dosing visits and the values obtained are within 30 μm. The CST value obtained at the latter visit serves as the new reference CST. †The mean of the 3 best BCVA scores obtained at any previous active dosing visit. ETDRS = Early Treatment Diabetic Retinopathy Study.

Figure 4

Graphs showing that low anti–vascular endothelial growth factor (VEGF) injection frequency in clinical practice versus clinical trials correlates with suboptimal outcomes. Adapted from Ciulla TA, Pollack JS, Williams DF. Br J Ophthalmol. 2021;105:216–221. Adapted under the terms of the CC BY-NC 4.0 license. DME = diabetic macular edema.