Letrozole for Treatment of Uterine Fibroids: A randomized, placebo-controlled trial

来曲唑治疗子宫肌瘤：一项随机、安慰剂对照试验

• 批准号: 10718036
• 负责人: Alison Huang
• 金额: $ 69.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718036
• 关键词: Accounting; Adverse effects; Adverse event; Age; Aromatase; Aromatase Inhibitors; Back; Biological; Blinded; Caring; Cells; Clinical; Clinical Data; Clinical Research; Clinical Trials; Control Groups; Data; Development; Disease; Dose; Drug usage; Economics; Enrollment; Enzymes; Estrogens; FDA approved; Fibroid Tumor; Follow-Up Studies; Functional disorder; Goals; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Growth; Hemorrhage; Hormonal; Hormone Antagonists; Hormone use; Hormones; Hot flushes; Hypertension; Hysterectomy; Infertility; Intestines; Letrozole; Long-Term Effects; Mediating; Medical; Menopause; Operative Surgical Procedures; Oral; Outcome; Ovarian; Ovarian hormone; Ovary; Participant; Patients; Pelvic Pain; Pelvis; Pharmaceutical Preparations; Phase; Placebos; Population; Population Heterogeneity; Postoperative Period; Premenopause; Procedures; Production; Progestins; Quality of life; Questionnaires; Randomized; Recovery; Reporting; Risk; Safety; Serum; Smooth Muscle Tumor; Source; Symptoms; Testing; Time; Uncontrolled Study; Uterine Fibroids; Uterine myomectomy; Uterus; Woman; Work; adverse pregnancy outcome; autocrine; black women; care costs; clinical outcome assessment; disability; efficacy evaluation; ethnic diversity; follow-up; hormone therapy; improved; novel; novel therapeutics; open label; paracrine; placebo controlled trial; preference; pressure; racial diversity; randomized placebo controlled trial; reduce symptoms; safety assessment; side effect; social; symptomatic improvement; tumor; ultrasound; urinary

PROJECT SUMMARY Uterine fibroids are smooth muscle tumors that occur in >80% of Black women and 70% of white women by age 50 years. Fibroids cause heavy menstrual bleeding, pelvic pain or pressure, urinary and bowel dysfunction, infertility, and adverse pregnancy outcomes. Major surgery with hysterectomy and myomectomy is the most common fibroid treatment, but surgery generally requires 2-6 weeks of recovery with substantial time off work and the inability to perform usual activities. To avoid surgery, many women prefer medical therapy for fibroids, but few options are available. There are only two FDA approved oral medications to treat fibroids, GnRH antagonists that block gonadotropins and diminish ovarian estrogen production akin to menopause. These medications require concomitant use of estrogen and progestin “add-back” therapy to mitigate hot flashes and other side effects and risks of low serum estrogen. Many women aim to avoid this long-term hormone therapy or have contraindications to hormone use. New medications that alleviate fibroid symptoms but avoid low serum estrogen are needed to improve care for women with fibroids. Fibroids are hormonally responsive tumors that decrease in volume when deprived of estrogen. The ovary is the primary source of estrogen in premenopausal women, but fibroid cells also produce local estrogen through activity of the aromatase enzyme. Through both autocrine and paracrine action, estrogen produced by fibroids demonstrates local control over fibroid growth. Letrozole is an aromatase inhibitor (AI) that blocks estrogen synthesis within fibroid cells. Therefore, letrozole may decrease fibroid volume and improve symptoms. Low doses of letrozole will inhibit the modest aromatase activity within fibroids, but not significantly block the robust aromatase activity in the ovaries of premenopausal women. Letrozole may serve as a novel therapy that improves fibroid symptoms without adverse effects of low serum estrogen. Despite a biologic mechanism to support AIs as a fibroid treatment, clinical data is very limited. In a few small uncontrolled studies, fibroid volume decreased 35-55% during 8-12 weeks of treatment. We recently completed a pilot, randomized, placebo-controlled trial of letrozole. The letrozole group had greater improvement in fibroid symptoms and quality of life compared with the placebo during 2 months of treatment and reported few side effects. Building on this preliminary data, we propose a full scale randomized, blinded, placebo-controlled trial that is powered to detect clinically meaningful changes in fibroid symptoms and fibroid volume. We will enroll 140 racially and ethnically diverse premenopausal women randomly assigned to oral letrozole 2.5mg/day or an identical placebo for 3 months and assess clinical outcomes and the development of adverse events. We will also evaluate long-term letrozole use with an open-label follow-up phase for up to 6 months of letrozole therapy. This trial will provide gold standard evidence to evaluate the efficacy of a novel treatment for uterine fibroids that has significant advantages over existing medication.

项目摘要 子宫纤维是平滑肌肿瘤，> 80％的黑人女性和70％的白色 妇女到50岁。肌瘤引起重量大量出血，骨盆疼痛或压力，尿液和肠 功能障碍，不育和不良妊娠结局。子宫切除术和肌瘤切除术的重大手术是 最常见的纤维化治疗方法，但手术通常需要2-6周的恢复时间 下班和无法进行常规活动。为了避免手术，许多女性更喜欢医疗治疗 肌瘤，但几乎没有选择。只有两种FDA批准的口服药物来治疗肌瘤， GNRH拮抗剂阻断促性腺激素并减少类似于绝经的卵巢雌激素产生。 这些药物需要伴随使用雌激素和孕激素“添加”疗法来减轻热 闪烁和其他副作用以及低血清雌激素的风险。许多妇女旨在避免长期 马龙疗法或使用马对的禁忌症。减轻肌瘤的新药物 症状但需要避免低血清雌激素来改善纤维女性的护理。 肌瘤是荷尔蒙反应型肿瘤，当缺乏雌激素时，体积减少。这 卵巢是绝经前女性雌激素的主要来源，但肌瘤细胞也会产生局部雌激素 通过芳香酶的活性。通过自分泌和旁分泌作用，由 肌瘤证明了局部对肌瘤生长的控制。 letrozole是一种阻断的芳香酶抑制剂（AI） 肌病细胞中的雌激素合成。因此，letrozole可能会减少肌瘤的体积并改善 症状。低剂量的letrozole会抑制肌瘤内的适度芳香化酶活性，但没有显着 阻止绝经前妇女的卵巢中强大的芳香​​化酶活性。 letrozole可以用作小说 可以改善低血清雌激素不良影响的纤维化症状的治疗。 尽管具有支持AIS作为纤维化治疗的生物学机制，但临床数据仍非常有限。在一些 在8-12周的治疗期间，少量的未控制研究，肌瘤的体积降低了35-55％。我们最近 完成了letrozole的试验，随机，安慰剂对照试验。 letrozole群有更大的 在治疗2个月内，与安慰剂相比，纤维化症状和生活质量的改善 并报告的副作用很少。在此初步数据的基础上，我们提出了一个随机，盲目的完整规模， 安慰剂对照试验有动力检测肌瘤症状和肌瘤的临床意义变化 体积。我们将在随机分配给口服的140名范围和种族多样的绝经前妇女 letrozole 2.5mg/天或相同的安慰剂3个月，评估临床结果和发展 不利事件。我们还将通过开放标签的随访阶段评估长期的letrozole用途，最多6 letrozole疗法的月份。该试验将提供黄金标准证据，以评估 与现有药物相比，对子宫纤维的新型治疗方法具有显着优势。