primary endpoint, CBFV change from baseline to Week 24, was significantly greater with voxelotor (least-squares mean change: voxelotor [n = 114] −12.06 cm/s, placebo [n = 108] −4.29 cm/s; difference −7.77 cm/s; 95% CI −13.18 to −2.37; p = 0.0048), with significant difference sustained through Week 48. Hemoglobin levels increased at Weeks 24 and 48 with voxelotor. Drug administration was paused in May 2024 when an imbalance of deaths was observed between treatment groups; subsequently, the trial discontinued when all active voxelotor trials were discontinued in September 2024. At study end, median (range) exposure was 84 (3–104) weeks for voxelotor and 84 (3–106) weeks for placebo. The most common SCD-related treatment-emergent adverse event was sickle cell anemia with crisis (voxelotor 59.2%; placebo 37.9%). All deaths (voxelotor n = 8; placebo n = 2) were considered unrelated to study drug by treating investigators. Overall, voxelotor showed CBFV reduction in children with SCD and conditional CBFV, suggesting HbS polymerization inhibition has a potential therapeutic role for this group; nevertheless, additional studies evaluating potential regional risks for sickle cell anemia with crisis or mortality are warranted.