Phase 2b Study of Denosumab to Prevent Bone Loss in Idiopathic Osteoporosis in Premenopausal Women Treated with Teriparatide

狄诺塞麦 (Denosumab) 预防接受特立帕肽治疗的绝经前妇女特发性骨质疏松症骨丢失的 2b 期研究

• 批准号: 9282269
• 负责人: Elizabeth J Shane
• 金额: $ 40.37万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282269
• 关键词: Phase; 2b; Study; Denosumab; Prevent

Osteoporosis that affects young, otherwise healthy women with intact gonadal function and no secondary cause of bone loss (idiopathic osteoporosis or IOP) is uncommon with an estimated prevalence in the United States of <200,000, based on fragility fractures or low bone mineral density (BMD). Our prior work defined abnormal skeletal microstructure in premenopausal IOP: thin, porous cortices, fewer, thinner, disconnected trabeculae, and reduced stiffness or strength. There is no FDA-approved therapy for premenopausal women with IOP, many of whom have multiple fractures or extremely low BMD. We are currently enrolling 41 premen- opausal women with IOP into a randomized, 24-month, two-site, FDA Orphan Diseases Program-funded trial “A Phase 2 Study of Teriparatide for the Treatment of Idiopathic Osteoporosis in Premenopausal Women” (FD003902; PI, Shane). We hypothesize that teriparatide (TPTD), which increases bone formation, will in- crease areal and volumetric BMD, restore abnormal microarchitecture towards normal, and increase bone strength in premenopausal IOP. However, emerging data from an earlier, open-label pilot study of TPTD in premenopausal IOP indicates that TPTD-associated gains in BMD begin to dissipate by 18-24 months after completion. Thus, we believe FD003902 participants will require antiresorptive therapy after completing TPTD to maintain improvements in bone density and quality. Denosumab (Prolia®) is a fully human monoclonal anti- body to receptor activator of nuclear factor-κβ ligand (RANKL) that inhibits development and activity of osteo- clasts, decreases bone resorption, increases BMD and lowers fracture rates. It is FDA-approved for postmen- opausal and male osteoporosis. We hypothesize that denosumab, initiated after completing two years of TPTD, will maintain or improve areal and volumetric BMD, microstructure and stiffness of the central and pe- ripheral skeleton in premenopausal women with IOP. We will test this hypothesis in a 24-month study of deno- sumab (60mg SC every 6 months). The 41 subjects participating in FD003902 will not provide sufficient power for a randomized trial. Thus we propose an open-label, Phase IIB study to estimate effects of denosumab on BMD, microstructure and stiffness, which will provide preliminary data to design a future randomized study. The Specific Aims are to estimate effects of denosumab on Aim 1) Areal BMD by DXA of the spine, hip, fore- arm; Aim 2) Total and trabecular volumetric BMD and stiffness of the spine by central QCT and finite element analysis (FEA); Aim 3) Total, cortical and trabecular volumetric BMD, trabecular microarchitecture, cortical po- rosity and stiffness of the distal radius and tibia by high resolution peripheral QCT (HR-pQCT) and FEA; and Aim 4) Serum PTH and bone turnover markers and associations between these variables and effects of deno- sumab on BMD, microarchitecture and stiffness. By investigating therapy for and improving the health of young women with IOP, this proposal addresses a key goal of the Office of Orphan Product Development grant pro- gram: to support clinical development of products for rare diseases/conditions where no current therapy exists.

骨质疏松症，影响年轻，其他健康的女性，性腺功能完整，没有继发性 骨丢失的原因（特发性骨质疏松症或IOP）在美国并不常见， <200，000的状态，基于脆性骨折或低骨矿物质密度（BMD）。我们之前的工作定义了 绝经前IOP中的异常骨骼微结构：薄、多孔皮质、较少、较薄、不连续 骨小梁和刚度或强度降低。没有FDA批准的治疗绝经前妇女的方法 患有IOP的患者，其中许多人有多处骨折或极低的BMD。我们目前正在招募41名预科生- 将患有IOP的女性纳入一项随机、24个月、两个地点、FDA孤儿疾病项目资助的试验 “特立帕鲁肽治疗绝经前女性特发性骨质疏松症的II期研究” （FD003902; PI，Shane）。我们假设，增加骨形成的teriparlitazone（TPTD），将在- 增加面积和体积BMD，使异常微结构恢复正常，并增加骨密度 绝经前IOP强度。然而，来自早期TPTD开放标签初探性研究的新数据显示， 绝经前IOP表明TPTD相关的BMD增加开始在绝经后18-24个月消失， 建成因此，我们认为FD 003902受试者在完成TPTD后需要抗吸收治疗 以保持骨密度和质量的改善。狄诺塞单抗（Prolia®）是一种全人单克隆抗- 核因子-κβ受体激活因子配体（RANKL）抑制骨形成和活性， 减少骨吸收，增加骨密度，降低骨折率。这是食品药品管理局批准的邮递员用的 骨质疏松症和男性骨质疏松症。我们假设在完成两年的治疗后开始使用地舒单抗， TPTD，将维持或改善区域和体积BMD，显微结构和刚度的中心和pe。 绝经前IOP妇女的外周骨骼。我们将在一项为期24个月的研究中验证这一假设， 单抗（60 mg SC，每6个月一次）。参与FD 003902的41例受试者将无法提供足够的把握度 进行随机试验因此，我们提出了一项开放标签、IIB期研究，以评估地舒单抗对 BMD、微观结构和刚度，这将为设计未来的随机研究提供初步数据。 具体目的是估计地舒单抗对目标1）脊柱、髋关节、前腰椎和股骨的DXA面积BMD的影响。 2）通过中心QCT和有限元法测量脊柱的总骨密度和骨小梁体积骨密度以及刚度 目的3）总骨密度、皮质骨密度和骨小梁体积骨密度、骨小梁微结构、皮质骨密度和骨小梁体积骨密度。 通过高分辨率外周QCT（HR-pQCT）和FEA测量桡骨远端和胫骨的粗糙度和刚度;以及 目的4）血清PTH和骨转换标志物以及这些变量与去甲肾上腺素效应之间的相关性。 单抗对BMD、微结构和刚度的影响。通过研究治疗和改善年轻人的健康， 该提案解决了孤儿产品开发办公室赠款的一个关键目标， gram：支持用于目前尚无治疗方法的罕见疾病/病症的产品的临床开发。