Background

Uterine fibroids are common non-cancerous neoplasm that cause heavy menstrual bleeding and other signs. Linzagolix is an oral gonadotropin-releasing hormone receptor antagonist taken once per day that dose-dependently suppresses gonadal steroids and might reduce uterine-fibroid-associated signs. Two phase 3 trials were conducted to confirm the efficacy and safety of linzagolix at full-suppression (200 mg) and partial-suppression (100 mg) doses with or without hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate) compared with placebo for the treatment of symptomatic uterine fibroids.

Methods

PRIMROSE 1 and PRIMROSE 2 were identical 52-week, randomised, parallel, double-blind, placebo-controlled, phase 3 trials conducted at clinics in the USA (PRIMROSE 1) and Europe and the USA (PRIMROSE 2). Eligible women with uterine fibroid-associated heavy menstrual bleeding (menstrual blood loss >80 mL per cycle) were randomly assigned in a 1:1:1:1:1 ratio to one of five masked treatments: (1) placebo, (2) 100 mg linzagolix per day alone, (3) 100 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate), (4) 200 mg linzagolix per day alone, or (5) 200 mg linzagolix per day with once-per-day hormonal add-back therapy (1 mg oestradiol and 0·5 mg norethisterone acetate). The primary endpoint was a response (menstrual blood loss ≤80 mL and ≥50% reduction from baseline) at 24 weeks in women who received at least one dose of treatment and did not meet any exclusion criteria based on predosing assessments. These trials are registered with ClinicalTrials.gov (NCT03070899 and NCT03070951). The trials have been completed.

Findings

Between May, 2017, and October, 2020, in PRIMROSE 1, 574 women were enrolled, of which 48 discontinued and 15 were excluded; therefore, 511 women were included in the full analysis set; and in PRIMROSE 2, 535 women were enrolled, of which 24 did not receive the study drug and ten women were excluded from the study, resulting in 501 women being included in the full analysis set. In both trials, a significantly higher proportion of women had a reduction in heavy menstrual bleeding in all linzagolix (with or without add-back therapy) treatment groups compared with the placebo group (p≤0·003). In PRIMROSE 1, the response rates were 56·4% (95% CI 45·8–66·6%) in the 100 mg group, 66·4% (56·6–75·2%) in the 100 mg plus add-back therapy group, 71·4% (61·8–79·8%) in the 200 mg group, and 75·5% (66·0–83·5%) in the 200 mg plus add-back therapy group, compared with 35·0% (25·8–45·0%) in the placebo group. In PRIMROSE 2, the response rates were 56·7% (46·3–66·7%) in the 100 mg group, 77·2% (67·8–85·0%) in the 100 mg plus add-back therapy group, 77·7% (68·4–85·3%) in the 200 mg group, and 93·9% (87·1–97·7%) in the 200 mg plus add-back therapy group, compared with 29·4% (20·8–39·3%) with placebo. The most common adverse events up to 24 weeks were hot flushes (35% of participants in PRIMROSE 1 and 32% in PRIMROSE 2 with linzagolix [200 mg] alone and 3–14% in all other groups).

Interpretation

Linzagolix (100 mg or 200 mg) with or without add-back therapy significantly reduced heavy menstrual bleeding. Partial suppression with once-per-day linzagolix (100 mg) without add-back therapy potentially provides a unique option for the chronic treatment of symptomatic uterine fibroids in women who cannot or do not want to take concomitant hormonal add-back therapy.

Funding

ObsEva.

中文翻译：

---

Linzagolix 联合或不联合激素反加疗法治疗症状性子宫肌瘤：两项随机、安慰剂对照、3 期试验

背景

子宫肌瘤是常见的非癌性肿瘤，会导致大量月经出血和其他症状。Linzagolix 是一种口服促性腺激素释放激素受体拮抗剂，每天服用一次，剂量依赖性地抑制性腺类固醇，并可能减少子宫肌瘤相关症状。进行了两项 3 期试验，以确认 linzagolix 在完全抑制（200 mg）和部分抑制（100 mg）剂量下加或不加激素反加疗法（1 mg 雌二醇和 0·5 mg 醋酸炔诺酮）的疗效和安全性) 与安慰剂相比，用于治疗有症状的子宫肌瘤。

方法

PRIMROSE 1 和 PRIMROSE 2 是相同的 52 周、随机、平行、双盲、安慰剂对照的 3 期试验，在美国 (PRIMROSE 1) 和欧洲和美国 (PRIMROSE 2) 的诊所进行。符合条件的患有与子宫肌瘤相关的大量月经出血（每个周期的月经失血量 > 80 mL）的女性以 1:1:1:1:1 的比例被随机分配至以下五种隐蔽治疗中的一种：(1) 安慰剂，(2)每天单独服用 100 mg linzagolix，(3) 每天服用 100 mg linzagolix，每天进行一次激素补充疗法（1 mg 雌二醇和 0·5 mg 醋酸炔诺酮），(4) 每天单独服用 200 mg linzagolix，或(5) 每天 200 mg linzagolix 和每天一次的激素反加疗法（1 mg 雌二醇和 0·5 mg 醋酸炔诺酮）。主要终点是接受至少一剂治疗且未满足基于给药前评估的任何排除标准的女性在 24 周时的反应（月经失血量≤80 mL，与基线相比减少 ≥50%）。这些试验已在 ClinicalTrials.gov 注册（NCT03070899 和 NCT03070951）。试验已经完成。

发现

在 2017 年 5 月至 2020 年 10 月期间，PRIMROSE 1 中有 574 名女性入组，其中 48 人停药，15 人被排除在外；因此，完整分析集中包含 511 名女性；在 PRIMROSE 2 中，535 名女性被纳入研究，其中 24 名未接受研究药物，10 名女性被排除在研究之外，导致 501 名女性被纳入完整分析集。在这两项试验中，与安慰剂组相比，在所有 linzagolix（有或无反加疗法）治疗组中，女性大量月经出血的比例显着增加（p≤0·003）。在 PRIMROSE 1 中，100 mg 组的缓解率为 56·4% (95% CI 45·8–66·6%)，100 mg plus 组的缓解率为 66·4% (56·6–75·2%)反加疗法组，200 mg 组为 71·4% (61·8–79·8%)， 200 mg 加反加疗法组为 75·5% (66·0–83·5%)团体，安慰剂组为 35·0% (25·8–45·0%)。在 PRIMROSE 2 中，100 mg 组的反应率为 56·7% (46·3–66·7%)，100 mg 加回加组的反应率为 77·2% (67·8–85·0%)与治疗组相比，200 mg 组为 77·7% (68·4–85·3%)，200 mg 加反加疗法组为 93·9% (87·1–97·7%) 29·4% (20·8–39·3%) 与安慰剂。长达 24 周最常见的不良事件是潮热（PRIMROSE 1 的参与者为 35%，PRIMROSE 2 的参与者为 32%，单独使用 linzagolix [200 mg]，所有其他组为 3-14%）。安慰剂组为 29·4% (20·8–39·3%)。长达 24 周最常见的不良事件是潮热（PRIMROSE 1 的参与者为 35%，PRIMROSE 2 的参与者为 32%，单独使用 linzagolix [200 mg]，所有其他组为 3-14%）。安慰剂组为 29·4% (20·8–39·3%)。长达 24 周最常见的不良事件是潮热（PRIMROSE 1 的参与者为 35%，PRIMROSE 2 的参与者为 32%，单独使用 linzagolix [200 mg]，所有其他组为 3-14%）。

解释

Linzagolix（100 毫克或 200 毫克）加或不加反加疗法显着减少月经过多。每天一次的 linzagolix（100 mg）不加回加疗法的部分抑制可能为不能或不想同时接受激素反加疗法的女性的症状性子宫肌瘤的慢性治疗提供独特的选择。

资金

ObsEva。