RCT of GnRH-a for ovarian protection during CYC therapy for rheumatic disease

描述(申请人提供)：这是一项多中心随机对照试验(RCT)，旨在测试这样一种假设，即与安慰剂相比，使用促性腺激素释放激素激动剂(GnRH-a)治疗育龄妇女在接受环磷酰胺治疗严重风湿性疾病时，可以减少卵巢损伤。根据循证方案，年龄在18-40岁之间的女性需要每天口服或间歇脉冲环磷酰胺治疗严重风湿性疾病，包括狼疮性肾炎、韦格纳肉芽肿、其他形式的低免疫性血管炎以及合并硬皮病的严重间质性肺部疾病。患者将在五个学术中心登记，主要临床项目集中在狼疮、脉管炎和硬皮病。GnRH-a或安慰剂将根据环磷酰胺治疗的持续时间进行3-6个月的治疗。干预期间和干预后6个月的纵向随访将评估卵巢储备的生物标志物，包括抗苗勒氏激素(AMH)、卵泡刺激素(FSH)以及超声测量卵巢体积和有腔卵泡计数。计划进行长期随访，以评估月经周期参数、怀孕次数和结局以及卵巢衰竭的时间。主要的结果衡量标准将是GnRH-a组与安慰剂组的AMH水平。AMH是一种有效的卵巢储备和受精能力的标志物，我们已经证明，在服用环磷酰胺后，根据年龄和环磷酰胺的累积剂量进行调整后，这一指标会降低。选择这一结果是为了检测可能经历卵巢功能下降但不是明显卵巢衰竭的女性的治疗效果。次要结果包括GnRH-a对卵巢功能的其他参数的影响，包括FSH、月经周期、卵巢体积和有腔卵泡计数。这将是GnRH-a在烷化剂治疗风湿性疾病期间用于卵巢保护的第一次随机对照试验。研究风湿病人群的优势包括年龄较小，只接触一种化疗药物。积极的结果可能会通过保留生殖能力和防止过早退出激素，显著改善许多接受环磷酰胺治疗的风湿病或癌症女性的生活质量。此外，这将是第一个测试卵巢功能替代标记物预测化疗导致的卵巢早衰后续发展的能力的随机对照试验，并评估GnRH-a的潜在保护作用。这些信息将有助于指导妇女和她们的医生在需要保留卵巢功能的情况下决定是否使用烷化剂。 公共卫生相关性：卵巢早衰，或更年期提前，是一些用于治疗自身免疫性或风湿性疾病(包括狼疮、血管炎和硬皮病)和癌症(包括乳腺癌)的化疗的毁灭性副作用。这项拟议的临床试验将评估一种药物(醋酸亮丙瑞林，一种促性腺激素释放激素激动剂)保护风湿病患者接受特定类型化疗(环磷酰胺)的卵巢的能力。预防卵巢早衰不仅对保持生育能力很重要，而且对降低与绝经早期相关的其他健康问题的风险也很重要，如心血管疾病、骨质疏松症和总死亡率。

DESCRIPTION (provided by applicant): This is a multicenter randomized controlled trial (RCT) to test the hypothesis that treatment with a gonadotropin-releasing hormone agonist (GnRH-a) reduces ovarian injury versus placebo in women of reproductive age being treated with cyclophosphamide for severe rheumatic diseases. Women ages 18-40 years who require administration of daily oral or intermittent pulse cyclophosphamide according to evidence-based protocols for treatment of severe rheumatic diseases including lupus nephritis, Wegener's granulomatosis, other forms of pauci-immune vasculitis, and severe interstitial lung disease complicating scleroderma will be entered into the trial. Patients will be enrolled at five academic centers with major clinical programs focused on lupus, vasculitis and scleroderma. GnRH-a or placebo will be administered for 3-6 months depending on the duration of cyclophosphamide therapy. Longitudinal follow-up during the intervention and 6 months post-intervention will assess biomarkers of ovarian reserve, including anti-mullerian hormone (AMH), FSH, and ultrasound measurement of ovarian volume and antral follicle counts. Long-term follow-up is planned to assess menstrual cycle parameters, the number and outcome of pregnancies, and time to ovarian failure. The primary outcome measure will be AMH levels in the GnRH-a vs. placebo groups. AMH is a validated marker of ovarian reserve and fecundability that we have shown to be reduced after cyclophosphamide administration, adjusting for age and cumulative cyclophosphamide dose. This outcome was chosen to enable detection of treatment effect in women who may experience decline in ovarian function but not overt ovarian failure. Secondary outcomes include the effect of GnRH-a on other parameters of ovarian function including FSH, menstrual cyclicity, ovarian volume and antral follicle counts. This will be the first RCT of GnRH-a for ovarian protection during alkylating agent treatment for rheumatic diseases. Advantages of studying the rheumatic disease population include young age and exposure to only one chemotherapeutic agent. A positive result could lead to significantly improved quality of life for many women with rheumatic diseases or cancer treated with cyclophosphamide, by preserving reproductive capacity and preventing premature hormone withdrawal. In addition, this will be the first RCT to test the ability of surrogate markers of ovarian function to predict subsequent development of chemotherapy-induced premature ovarian failure and assess the potentially protective effects of GnRH-a. This information will help guide women and their physicians making decisions regarding use of alkylating agents when preservation of ovarian function is desired. PUBLIC HEALTH RELEVANCE: Premature ovarian failure, or early menopause, is a devastating side effect of some chemotherapies used for the treatment of autoimmune or rheumatic conditions (including lupus, vasculitis, and scleroderma) and cancers (including breast cancer). The proposed clinical trial will evaluate the ability of a drug (leuprolide acetate, which is a gonadotropin-releasing hormone agonist) to protect ovaries in patients receiving a specific type of chemotherapy (cyclophosphamide) for rheumatic diseases. Prevention of premature ovarian failure is important not only to preserve fertility, but also to reduce risk of other health problems associated with early menopause, such as cardiovascular disease, osteoporosis, and overall mortality.