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Objective: To study the timing of the effect of linzagolix, an oral GnRH antagonist, on significant reduction in heavy menstrual bleeding (HMB) in women with uterine fibroids., Design: The study used pooled data from PRIMROSE1 and PRIMROSE2, two double-blind, similar placebo-controlled trials of linzagolix in US and Europe, respectively. Eligible participants were randomized equally across four treatment arms (linzagolix 100mg and 200mg, with and without concomitant hormonal add-back therapy [ABT] consisting of 1 mg estradiol and 0.5 mg norethisterone acetate) and one placebo arm. The cumulative incidence of achieving clinically significant HMB reduction and maintaining it to week 24 was compared between the linzagolix arms and the placebo arm using Kaplan-Meier plots adjusted for confounding by race and study (PRIMROSE1 vs PRIMROSE2)., Subjects: The PRIMROSE trials randomized 1,012 women aged ≥18 years with ultrasound-confirmed uterine fibroids and HMB., Intervention: Linzagolix (100mg and 200mg, with and without hormonal add-back therapy) versus placebo., Main Outcome Measures: The main outcome of this analysis was the time to achievement of clinically significant HMB reduction and its maintenance up to week 24., Results: The onset of action in achieving and maintaining clinically significant HMB reduction was significantly more rapid for the linzagolix treatment arms than for the placebo arm, with a median time of <4 weeks for most linzagolix doses (except 100mg alone). The fastest onset was seen with linzagolix 200mg with or without ABT doses, with a median time of only 3 days. The cumulative incidence of achieving clinically significant HMB reduction by week 4 and maintaining it to week 24 was also significantly higher for the linzagolix treatment arms than the placebo arm. Specifically, across the four linzagolix treatment arms, 23.2% to 68.1% achieved clinically significant HMB reduction by week 4 and maintained it to week 24 versus 7.8% for placebo arm., Conclusion: Linzagolix was associated with a quick effect on reducing clinically significant HMB compared to placebo. Linzagolix thus offers a novel non-invasive treatment approach for the rapid management of HMB symptoms in patients with uterine fibroids., (Copyright © 2025. Published by Elsevier Inc.)