Dataset Information

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.

SUBMITTER: Eter N

PROVIDER: S-EPMC9559760 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Eter Nicole N Singh Rishi P RP Abreu Francis F Asik Kemal K Basu Karen K Baumal Caroline C Chang Andrew A Csaky Karl G KG Haskova Zdenka Z Lin Hugh H Ruiz Carlos Quezada CQ Ruamviboonsuk Paisan P Silverman David D Wykoff Charles C CC Willis Jeffrey R JR

Ophthalmology science 20211230 1

<h4>Purpose</h4>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 d ...[more]

PMID: 36246184

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Project description:PurposeTo describe the design and rationale of the phase 3 TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) trials that aimed to assess efficacy, safety, and durability of faricimab, the first bispecific antibody for intraocular use, which independently binds and neutralizes both angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A) versus aflibercept in patients with neovascular age-related macular degeneration (nAMD).DesignIdentical, global, double-masked, randomized, controlled, phase 3 clinical trials.ParticipantsAdults with treatment-naïve nAMD.MethodsThese trials were designed to evaluate patients randomized to receive faricimab 6.0 mg up to every 16 weeks after 4 initial every-4-week doses or aflibercept 2.0 mg every 8 weeks after 3 initial every-4-week doses. The initial doses in the faricimab arm were followed by individualized fixed treatment intervals up to week 60, based on disease activity assessment at weeks 20 and 24, guided by central subfield thickness, best-corrected visual acuity (BCVA), and investigator assessment. The primary efficacy end point was BCVA change from baseline averaged over weeks 40, 44, and 48. Secondary end points included the proportion of patients receiving every-8-week, every-12-week, and every-16-week faricimab and anatomic outcomes. Safety outcomes included incidence and severity of ocular and nonocular adverse events. From week 60, faricimab-treated patients followed a personalized treatment interval (PTI), a novel protocol-driven treat-and-extend regimen with interval adjustment from every 8 weeks to every 16 weeks based on individualized treatment response measured by anatomic criteria, functional criteria, and investigator assessment of patients' disease activity.Main outcome measuresRationale for trial design and PTI approach.ResultsThe TENAYA and LUCERNE trials were the first registrational trials in nAMD to test fixed dosing regimens up to every 16 weeks based on patients' disease activity in year 1 and incorporate a PTI paradigm during year 2. The PTI approach was designed to tailor treatment intervals to individual patient needs, to reflect clinical practice treatment practice, and to reduce treatment burden.ConclusionsThe innovative trial design rationale for the TENAYA and LUCERNE trials included maximizing the benefits of angiopoietin-2 blockade through dosing up to every 16 weeks and PTI regimens based on patients' disease activity while fulfilling health authority requirements for potential registrational efforts.

Project description:PurposeTo describe the rationale and design of the VOYAGER (NCT05476926) study, which aims to investigate the safety and effectiveness of faricimab and the Port Delivery System with ranibizumab (PDS) for neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) in clinical practice. VOYAGER also aims to understand drivers of clinical practice treatment outcomes by gaining novel insight into the intersection of treatment regimens, decisions, anatomic outcomes, and vision.DesignPrimary data collection, noninterventional, prospective, multinational, multicenter clinical practice study.ParticipantsAt least 5000 patients initiating/continuing faricimab or PDS for nAMD/DME (500 sites, 31 countries).MethodsManagement will be per usual care, with no mandated scheduled visits/imaging protocol requirements. Using robust methodologies, relevant clinical and ophthalmic data, including visual acuity (VA), and data on treatment clinical setting/regimens/philosophies, presence of anatomic features, and safety events will be collected. Routinely collected fundus images will be uploaded to the proprietary Imaging Platform for analysis. An innovative investigator interface will graphically display the patient treatment journey with the aim of optimizing treatment decisions.Main outcome measuresPrimary end point: VA change from baseline at 12 months per study cohort (faricimab in nAMD and in DME, PDS in nAMD). Secondary end points: VA change over time and per treatment regimens (fixed, treat-and-extend, pro re nata, and other) and number. Exploratory end points: VA change in relation to presence/location of anatomic features that impact vision (fluid, central subfield thickness, fibrosis, atrophy, subretinal hyperreflective material, diabetic retinopathy severity, and disorganization of retinal inner layers) and per treatment regimen/philosophies. The impact of regional and practice differences on outcomes will be assessed as will safety.ResultsRecruitment commenced in November 2022 and will continue until late 2027, allowing for up to 5 years follow-up. Exploratory interim analyses are planned annually.ConclusionsVOYAGER is an innovative study of retinal diseases that will assess the effectiveness and safety of faricimab and PDS in nAMD and DME and identify clinician- and disease-related factors driving treatment outcomes in clinical practices globally to help optimize vision outcomes.Financial disclosuresProprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Project description:PurposeDual inhibition of angiopoietin-2 and VEGF-A with faricimab (Vabysmo) offers excellent visual acuity gains with strong durability in patients with diabetic macular edema (ME) and neovascular age-related macular degeneration. The phase III BALATON/COMINO (NCT04740905/NCT04740931) trials will investigate the efficacy, safety, and durability of faricimab in patients with ME due to retinal vein occlusion (RVO).DesignTwo identically designed global, randomized, double-masked, active comparator-controlled studies.ParticipantsAnti-VEGF treatment-naive patients with branch, central, or hemiretinal RVO.MethodsPatients were randomized to 6 monthly injections of faricimab 6.0 mg or aflibercept 2.0 mg. From weeks 24 to 72, all patients received faricimab 6.0 mg administered in up to 16-week intervals using an automated treatment algorithm to generate a treat-and-extend-based personalized treatment interval dosing regimen. Personalized treatment interval adjustments were based on changes in central subfield thickness (CST) and best-corrected visual acuity (BCVA).Main outcome measuresPrimary end point was noninferiority of faricimab versus aflibercept in mean change from baseline in BCVA (week 24; noninferiority margin: 4 letters). Secondary end points (weeks 0-24) were mean change from baseline in BCVA, CST, and National Eye Institute Visual Function Questionnaire 25 composite score; proportion of patients gaining or avoiding loss of ≥ 15/≥ 10/≥ 5/> 0 letters. Secondary end points (weeks 24-72) were treatment durability (week 68); continuation of weeks 0 to 24 end points. Ocular/nonocular adverse events will be assessed.ResultsIn total, 1282 patients across 22 countries were enrolled (BALATON, 553 patients, 149 centers; COMINO, 729 patients, 193 centers).ConclusionsUsing a novel automated interval algorithm, BALATON/COMINO will evaluate the efficacy and safety of faricimab for ME secondary to RVO and provide key insights into how to personalize treatment.Financial disclosuresProprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Dataset Information

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

Purpose

Design

Participants

Methods

Main outcome measures

Results

Conclusions

Publications

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

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