BALATON and COMINO: Phase III Randomized Clinical Trials of Faricimab for Retinal Vein Occlusion: Study Design and Rationale

Abstract

Purpose: Dual 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).

Design: Two identically designed global, randomized, double-masked, active comparator-controlled studies.

Participants: Anti-VEGF treatment-naive patients with branch, central, or hemiretinal RVO.

Methods: Patients 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 measures: Primary 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.

Results: In total, 1282 patients across 22 countries were enrolled (BALATON, 553 patients, 149 centers; COMINO, 729 patients, 193 centers).

Conclusions: Using 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 disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Keywords: Angiopoietin-2; Faricimab; Macular edema; Retinal vein occlusion; Vascular endothelial growth factor receptor.

Figure 1

BALATON and COMINO: study design overview. ^a The personalized treatment interval (PTI) is a protocol-driven treat-and-extend–based regimen. Patients previously randomized to aflibercept moved directly to faricimab PTI without receiving any loading doses. ^b Change from baseline in best-corrected visual acuity, as measured on the ETDRS chart at a starting distance of 4 m. Q4W = every 4 weeks; R = randomization.

Figure 2

BALATON and COMINO: Decision tree for interactive voice or web-based response system (IxRS)-determined personalized treatment interval (PTI) dosing intervals. ^a Initial reference central subfield thickness (CST) = CST value when the initial CST threshold criteria are met, no earlier than week 20. Reference CST is adjusted if CST decreases by > 10% from the previous reference CST for 2 consecutive faricimab dosing visits and the values obtained are within 30 μm. The CST value obtained at the latter visit serves as the new reference CST, starting immediately at that visit. ^b Reference best-corrected visual acuity (BCVA) = the mean of the 3 best BCVA scores obtained at any previous active dosing visit. Q4W = every 4 weeks; Q16W = every 16 weeks.

Figure 3

BALATON and COMINO: Personalized treatment interval (PTI) scenario examples. Horizontal line represents central subfield thickness (CST) threshold of 325 μm. A, week 20: CST < 325 μm (with no associated ≥ 10-letter best-corrected visual acuity [BCVA] decrease from reference BCVA), extend to every 8 weeks (Q8W); week 28: CST within ± 10% of reference CST^a (with no associated ≥ 10-letter BCVA decrease from reference BCVA^b), extend to every 12 weeks (Q12W); Week 40: CST within ± 10% of reference CST (with no associated ≥ 10-letter BCVA decrease from reference BCVA), extend to every 16 weeks (Q16W); Week 56: CST within ± 10% of reference CST (with no associated ≥ 10-letter BCVA decrease from reference BCVA) and patient is at the maximum treatment interval, maintain Q16W. B, week 20: CST < 325 μm (with no associated ≥ 10-letter BCVA decrease from reference BCVA), extend to Q8W; week 28: CST increased by > 10% and ≤ 20% of reference CST (with an associated BCVA increase), maintain at Q8W; week 36: CST within ± 10% of reference CST (with no associated ≥ 10-letter BCVA decrease from reference BCVA), extend to Q12W; week 48: CST within ± 10% of reference CST (with no associated ≥ 10-letter BCVA decrease from reference BCVA), extend to Q16W; week 64: CST within ± 10% of reference CST (with no associated ≥ 10-letter BCVA decrease from reference BCVA) and patient is at the maximum treatment interval, maintain Q16W. C, week 20: CST < 325 μm (with no associated ≥ 10-letter BCVA decrease from reference BCVA), extend to Q8W; week 28: CST within ± 10% of reference CST (with no associated ≥ 10-letter BCVA decrease from reference BCVA), extend to Q12W; week 40: CST within ± 10% of reference CST (with no associated ≥ 10-letter BCVA decrease from reference BCVA), extend to Q16W; week 56: CST increased by > 10% and ≤ 20% of reference CST (with an associated ≥ 10-letter BCVA decrease from reference BCVA), reduce to every 4 weeks (Q4W); week 60: CST within ± 10% of reference CST (with no associated ≥ 10-letter BCVA decrease from reference BCVA), extend to Q8W; week 68: CST within ± 10% of reference CST (with no associated ≥ 10-letter BCVA decrease from reference BCVA), extend to Q12W. D, week 20: CST < 325 μm (with no associated ≥ 10-letter BCVA decrease from reference BCVA), extend to Q8W; week 28: CST within ± 10% of reference CST (with no associated ≥ 10-letter BCVA decrease from reference BCVA), extend to Q12W; week 40: CST within ± 10% of reference CST (with no associated ≥ 10-letter BCVA decrease from reference BCVA), extend to Q16W; week 56: CST increased by > 10% and ≤ 20% of reference CST (with associated ≥ 5- and < 10-letter BCVA decrease from reference BCVA), reduce to Q12W; week 68: CST within ± 10% of reference CST (with no associated ≥ 10-letter BCVA decrease from reference BCVA), maintain Q12W (interval cannot be further extended given the previous interval reduction from Q16W). ^a The first CST value that is < 325 μm, starting at week 20. Reference CST is adjusted if CST decreases by > 10% from the previous reference CST for 2 consecutive faricimab dosing visits and the values obtained are within 30 μm. The CST value obtained at the latter visit serves as the new reference CST. ^b The mean of the 3 best BCVA scores obtained at any previous active dosing visit.