Phase 3, randomised, placebo-controlled trial of voxelotor for the resolution of leg ulcers in sickle cell disease: RESOLVE.

Abstract

Leg ulcers are a debilitating complication of sickle cell disease (SCD, including sickle cell anaemia and other sickle cell disorders) and have no proven treatments. Resolution of Sickle Cell Leg Ulcers with Voxelotor (RESOLVE) was a Phase 3, randomised, double-blind, placebo-controlled trial evaluating voxelotor for leg ulcer resolution in participants aged ≥12 years with SCD (homozygous haemoglobin S [HbSS]/haemoglobin S β⁰-thalassaemia [HbSβ⁰]) and ≥1 active cutaneous lower-extremity ulcer. Participants from Kenya, Nigeria and Brazil were randomised 1:1 to voxelotor 1500 mg (N = 45) or placebo (N = 43) for 12 weeks. The primary end-point, complete resolution of all target ulcer(s) at Week 12, was not met (achieved resolution: voxelotor 6.7% [3/45], placebo 7.0% [3/43]; two-sided p > 0.99). After Week 12, both groups received open-label voxelotor. During this period, dosing was paused in May 2024, when preliminary data from four voxelotor trials, including RESOLVE, showed safety signals and potential risks that required further analysis. The trial was discontinued in September 2024 when voxelotor was withdrawn from all markets globally. In final safety analyses for RESOLVE, the most common SCD-related treatment-emergent adverse event (TEAE) was sickle cell anaemia with crisis (randomised period: voxelotor 44.4%, placebo 25.6%; open-label period: continuing-voxelotor 60.5%, delayed-voxelotor 53.5%). Eleven participants had fatal events, nine when receiving voxelotor and two after voxelotor was paused (one after ~1 week; one after ~4 months); no deaths were considered treatment-related. In conclusion, leg ulcer resolution was similar between groups, and the voxelotor arm had a higher rate of TEAEs.