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

描述（由申请人提供）：这是一项多中心随机对照试验（RCT），旨在验证使用促性腺激素释放激素激动剂（GnRH-a）治疗严重风湿性疾病的育龄妇女，与安慰剂相比，使用促性腺激素释放激素激动剂（GnRH-a）治疗可减少卵巢损伤的假设。根据基于证据的方案，需要每日口服或间歇脉冲环磷酰胺治疗严重风湿性疾病（包括狼疮肾炎、韦格纳肉芽肿病、其他形式的少免疫血管炎和严重间质性肺疾病合并硬皮病）的18-40岁女性将进入试验。患者将在五个主要临床项目集中于狼疮、血管炎和硬皮病的学术中心登记。GnRH-a或安慰剂将根据环磷酰胺治疗的持续时间给予3-6个月。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，包括抗苗勒管激素（AMH）、卵泡刺激素（FSH）、卵巢体积和窦卵泡计数的超声测量。计划进行长期随访，以评估月经周期参数、妊娠次数和结局以及卵巢功能衰竭的时间。主要结果测量将是GnRH-a组与安慰剂组的AMH水平。AMH是卵巢储备和生育能力的有效标志，我们已经证明，在环磷酰胺给药后，根据年龄和累积环磷酰胺剂量调整，AMH会降低。选择这个结果是为了能够检测卵巢功能下降但没有明显卵巢功能衰竭的妇女的治疗效果。次要结局包括GnRH-a对卵巢功能其他参数的影响，包括FSH、月经周期、卵巢体积和窦卵泡计数。这将是GnRH-a在烷基化剂治疗风湿病期间卵巢保护的首个RCT。研究风湿病人群的优势包括年龄小和只暴露于一种化疗药物。一个积极的结果可以通过保持生殖能力和防止过早退出激素，大大改善许多患有环磷酰胺治疗的风湿性疾病或癌症的妇女的生活质量。此外，这将是第一个测试卵巢功能替代标记物预测化疗诱导的卵巢早衰后续发展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时决定是否使用烷基化剂。

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.