Exploratory Clinical Studies of Tenofovir and UC781 Gel and Film Including Ex Vivo

替诺福韦和 UC781 凝胶和薄膜（包括体外）的探索性临床研究

• 批准号: 8660269
• 负责人: Sharon L. Hillier
• 金额: $ 58.74万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660269
• 关键词: AIDS prevention; Affect; Anti-Bacterial Agents; Anti-Retroviral Agents; Antigens; Antiviral Agents; Biological Response Modifiers; Biopsy; Biopsy Specimen; Blood; Blood specimen; Carbohydrates; Cells; Clinical Protocols; Clinical Research; Coitus; Data; Defensins; Diagnostic; Dosage Forms; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Ecology; Effectiveness; Enrollment; Enzyme-Linked Immunosorbent Assay; Enzymes; Evaluation; Female; Film; Future; Gel; Genital system; Glycoproteins; Goals; Grant; HIV; HIV Infections; Human; Hysterectomy; Immune system; Immunohistochemistry; Irrigation; Laboratories; Lactoferrin; Local Microbicides; Measurement; Measures; Modeling; Mucins; Mucous body substance; Natural Immunity; Operative Surgical Procedures; Pharmaceutical Preparations; Phase; Placebos; Population Study; Procedures; Protocols documentation; Randomized; Safety; Sampling; Serum; Specimen; Structure; Tenofovir; Testing; Time; Tissue Sample; Tissues; UC 781; Vagina; Vaginal Gel; Water; Woman; antimicrobial; base; cervicovaginal; cytokine; efficacy testing; glycoprotein structure; healthy volunteer; in vivo; innovation; microbial; microbicide; novel; product development; protective effect; randomized placebo controlled trial; safety study; trial comparing; vaginal fluid; volunteer

The broad, long term goal of Project 3 is to compare the ex vivo efficacy and safety of film vs gel formulations pf two antiretroviral drugs being developed as topical microbicides. The overarching hypothesis is that gel and film formulations of tenofovir and UC781 will have efficacy agaist HIV in tissue explants from women exposed to these formulations, but there will be a differential impact of the two dosage forms on the vaginal ecology including genital mucus. Over the five year period, we will 1) establish the ex vivo HIV challenge model in biopsy samples, 2) compare the protective effect of vaginal gel and film formulations of tenofovir and UC781 against HIV in the ex vivo challenge model, 3) compare the effects of gel and film formulations of tenofovir and UC781 on the vginal ecology and 4) measure the levels of tenofovir and UC781 in the cervicovaginal lavage and blood samples obtained from women enrolled in the two Exploratory IND studies described in this project. For Aim 1, the ex vivo challenge model for ectocervical and vaginal biopsy samples will be developed in 20 volunteers during year 1. Two randomized, placebo-controlled trials comparing gel to film formulations of tenofovir and UC781 will be conducted in years 2-5 of the project period. These study populations will provide ectocervical biopsy tissue for evaluation of product efficacy against HIV ex vivo (Core B), as well as multiple measures of product safety and pharmacokinetic assessment of drug levels in blood and cervicovaginal lavage (Project 4). The impact of gel and film products on innate immunity of the female genital tract will be assessed by measuring innate antiviral and antibacterial activity of vaginal fluid before and after product exposure, assessment of the vaginal microflora, and measurement of innate immune mediators. Mucus and mucin-degrading enzymes present in the vaginal fluid before and after product exposure will be compared. At the conclusion of these studies, film formulations of UC781 and tenofovir will be posed to enter formal Phase 1 safety studies. This project relies on Project 4, Core A, Core B and Core C.

项目 3 的广泛长期目标是比较薄膜与凝胶的离体功效和安全性 两种抗逆转录病毒药物的制剂正在开发作为局部杀菌剂。总体假设 替诺福韦和 UC781 的凝胶和薄膜制剂对组织外植体中的 HIV 具有功效 接触这些制剂的女性，但两种剂型对女性的影响不同 阴道生态，包括生殖器粘液。在五年内，我们将 1) 建立离体 HIV 活检样本中的挑战模型，2) 比较阴道凝胶和薄膜制剂的保护作用 替诺福韦和UC781在离体攻击模型中对抗HIV，3）比较凝胶和薄膜的效果 替诺福韦和 UC781 制剂对阴道生态的影响，4) 测量替诺福韦和 UC781 的水平 从参加两个探索性 IND 的女性获得的宫颈阴道灌洗液和血液样本中 该项目中描述的研究。对于目标 1，宫颈外和阴道活检的离体挑战模型 第一年将在 20 名志愿者中开发样本。两项随机、安慰剂对照试验 比较替诺福韦和 UC781 的凝胶与薄膜制剂将在项目的第 2-5 年进行 时期。这些研究人群将提供宫颈外活检组织以评估产品功效 体外抗 HIV（核心 B），以及产品安全性和药代动力学的多项措施 评估血液和宫颈阴道灌洗液中的药物浓度（项目 4）。凝胶和薄膜产品的影响 将通过测量先天抗病毒和 产品暴露前后阴道液的抗菌活性，阴道微生物群的评估， 和先天免疫介质的测量。阴道中存在粘液和粘蛋白降解酶 将比较产品暴露之前和之后的液体。在这些研究的结论中，电影 UC781 和替诺福韦的制剂将进入正式的 1 期安全性研究。该项目依赖于 项目 4、核心 A、核心 B 和核心 C。