Linzagolix is a novel, oral GnRH receptor antagonist developed for the treatment of endometriosis and uterine fibroids. We assessed high-dose linzagolix safety and bleeding pattern effects in healthy women using combined versus delayed hormonal add-back therapy (ABT). This was a single-center, open-label, parallel-group study in 32 premenopausal women, who were randomized to daily linzagolix (200 mg)/ABT for 10 weeks ("Combined-ABT") or linzagolix (200 mg) for 4 weeks followed by linzagolix (200 mg)/ABT for 6 weeks ("Delayed-ABT"). Main outcome measures included bleeding records, trough estradiol (E2) concentrations and adverse events. Linzagolix alone promptly reduced bleeding, leading to amenorrhea in all women by week 5. When combined ABT was started (week 5), spotting (≤ 0.80 days/week/subject) and bleeding (≤ 0.53 days/week/subject) occurred; bleeding was markedly more frequent than after ABT start in the "Combined-ABT" group. In the "Combined-ABT" group, spotting (≤ 0.69 days/week/subject) and occasional bleeding (≤ 0.25 days/week/subject) occurred during the first half of treatment with a tendency to further decrease during the second half. Linzagolix alone rapidly reduced E2 reaching median week 4 levels of 4.1 pg/mL. Median E2 after combined linzagolix/ABT ranged between 35 and 42 pg/mL for the "Delayed-ABT" group (weeks 5-10) and between 24 and 32 pg/mL for the "Combined-ABT" group (weeks 1-10). Linzagolix was well tolerated. Most frequently reported adverse events were headache (32/156) and hot flushes (19/156). Hot flushes exclusively occurred in the "Delayed-ABT" group. In this study, treatment start with a combined linzagolix/ABT regimen resulted in better bleeding control, no hot flushes, and lower median E2 levels than a "Delayed-ABT" regimen. These results may help defining the linzagolix/ABT regimen to be adopted when treating sex-hormone-dependent diseases. Clinical Trial Registration Number-EudraCT Number: 2017-003822-34.
Keywords: Bleeding; Endometriosis; Linzagolix; Uterine fibroids.