Contraception development research center to advance a novel intravaginal ring as a non-hormonal multipurpose prevention technology

总体-摘要 人口理事会（PC）P50提案的总体目标是开发一种创新的非激素 多用途预防技术（MPT）阴道环（IVR），有可能改善患者的生活 全球数百万妇女通过与意外怀孕和性行为的重叠负担作斗争 包括艾滋病毒在内的性传播感染。最新数据显示，绝大多数女性更喜欢 预防怀孕和性传播感染/艾滋病毒的措施优于仅预防怀孕或性传播感染/艾滋病毒的措施。我们的“CZL-IVR”是 用户控制的30天IVR，包含三种活性药物成分（API），铜（C），醋酸锌 (Z)和丙交酯（L）（乳酸前药），它们一起具有非激素避孕和抗STI/HIV活性 包括衣原体（CT）、淋病（GC）、HSV-2和HIV-1。丙交酯可维持最佳阴道pH值， 抗菌、抗病毒和抗细菌性阴道病（BV）作用。我们将推进CZL-IVR的开发 通过实施三个综合研究项目。在项目1中，我们的目标是制定和制造 实现30天API递送的CZL-IVR，生产并表征 具有不同尺寸和聚合物的IVR，可选择四种具有一系列机械性能的候选产品 在最终用户研究中进行评估，并建立良好的生产规范（GMP）生产 用于在项目3中进行的研究的非药物环。在项目2中，我们的目标是定义最佳API 三种API单独和组合的递送剂量，并确认原型的有效性和安全性 CZL-IVR通过进行必要的临床前研究，包括体外和体内避孕有效性， API和原型人体大小和恒河猴大小的CZL的抗菌功效和毒性研究- IVRs。在项目3中，我们将通过最终用户研究更广泛地告知CZL-IVR开发和该领域 采用新的混合方法，包括对四种选定的 具有不同机械特性的候选非药物IVR，一项30天连续使用研究， 医疗原型IVR与嵌入式温度传感器，和一个全国性的横断面调查， 离散选择实验（DCE）和潜在类别分析（LCA）。行政核心将支持和 加强我们跨学科合作研究，提供科学、行政和业务方面的专门知识 和监督，并管理咨询委员会，以确保遵守时间表和成功实现我们的 目的是通过严谨的科学。我们的P50中心将成为培养早期研究人员职业生涯的中心， 通过奖学金和试点项目赠款鼓励MPT产品开发。从我们世界级的 生物医学研究中心和建立在几十年成功的避孕产品开发， PC的P50中心将利用丰富的，协作的，跨学科的环境和广阔的 PC和我们的合作伙伴的经验，以推进创新MPT产品的开发。

OVERALL – ABSTRACT The overarching goal of the Population Council’s (PC) P50 proposal is to develop an innovative non-hormonal multipurpose prevention technology (MPT) intravaginal ring (IVR) with the potential to improve the lives of millions of women globally by combatting the overlapping burdens of unintended pregnancy and sexually transmitted infections (STIs), including HIV. Emerging data indicate that women overwhelmingly prefer products that prevent pregnancy and STIs/HIV over ones that prevent only pregnancy or only STI/HIVs. Our ‘CZL-IVR’ is a user-controlled 30-day IVR containing three active pharmaceutical ingredients (APIs), copper (C), zinc acetate (Z), and lactide (L) (a lactic acid prodrug) that together have non-hormonal contraceptive and anti-STI/HIV activity including chlamydia (CT), gonorrhea (GC), HSV-2, and HIV-1. Lactide maintains optimal vaginal pH and provides antibacterial, antiviral, and anti-bacterial vaginosis (BV) effects. We will advance development of our CZL-IVR through implementation of three integrated research projects. In Project 1 we aim to formulate and manufacture CZL-IVRs that achieve 30-day API delivery, manufacture and characterize in vitro mechanical performance of IVRs with varying dimensions and polymers with the selection of four candidates with a range of mechanical characteristics to evaluate in end-user research, and establish Good Manufacturing Practice (GMP) production for non-medicated rings for research conducted in Project 3. In Project 2 we aim to define the optimal API delivery doses of the three APIs alone and in combination, and to confirm the efficacy and safety of the prototype CZL-IVR by conducting essential preclinical studies including in-vitro and in-vivo contraceptive efficacy and antimicrobial efficacy and toxicity studies of APIs and of prototype human-sized and rhesus macaque-sized CZL- IVRs. In Project 3 we will inform CZL-IVR development and the field more broadly through end-user research employing novel mixed method approaches including a controlled setting cross-over study of the four selected candidate non-medicated IVRs of varying mechanical characteristics, a 30-day continuous use study of a non- medicated prototype IVR with an embedded temperature sensor, and a national cross-sectional survey with a discrete choice experiment (DCE) and latent class analysis (LCA). The Administrative Core will support and synergize our interdisciplinary collaborative research, provide scientific, administrative, and operational expertise and oversight, and manage advisory committees to ensure adherence to timelines and success in achieving our aims through rigorous science. Our P50 Center will be a hub fostering careers of early stage investigators and inspiring MPT product development through fellowships and pilot project grants. Drawing from our world-class Center for Biomedical Research and building on decades of successful contraceptive product development, the PC’s P50 Center will capitalize on the rich, collaborative, and interdisciplinary environment and the vast experience of the PC and our partners to advance development of an innovative MPT product.