Project 3: PREVENT: A first-in-human clinical trial of Griffithsin, an HIV entry

项目 3：预防：HIV 药物 Griffithsin 的首次人体临床试验

• 批准号: 8769380
• 负责人: IAN Michael MCGOWAN
• 金额: $ 44.26万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8769380
• 关键词: AIDS prevention; Address; Affinity; Animals; Antigens; Antiviral Agents; Anus; Awareness; Binding; Biopsy; Carbopol; Cell surface; Cells; Clinical Trials; Clinical Trials Design; Community Health; Data; Data Set; Detection; Dimensions; Dose; Drug Exposure; Drug Formulations; Drug Kinetics; Environment; Epithelial; Epithelial Cells; Exposure to; Flow Cytometry; Gel; Gene Expression; Goals; HIV; HIV Entry Inhibitors; HIV Infections; HIV Receptors; HIV-1; HIV-2; Health; Hepatitis C virus; Human; Human Development; Immune; Immune response; Immunohistochemistry; In Vitro; Incidence; Inflammatory; Laboratories; Laboratory Animals; Lectin; Link; Lymphocyte; Measures; Metagenomics; Mucous Membrane; Mus; Natural Immunity; Oryctolagus cuniculus; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Phase I Clinical Trials; Placebo Control; Placebos; Plants; Polysaccharides; Prevention; Proteins; Proteomics; Randomized; Recruitment Activity; Rectum; Risk; Safety; Sampling; Simplexvirus; Staging; Structure; Surface; Systems Biology; T-Lymphocyte; Techniques; Tissues; Toxic effect; Vagina; Viral; adaptive immunity; base; crosslink; cytokine; design; healthy volunteer; human study; immunotoxicity; inhibitor/antagonist; men; men who have sex with men; microbial community; microbicide; microbiome; novel; preclinical safety; prevent; programs; prospective; rRNA Genes; rectal; rectal microbicide; response; transcriptomics; transmission process; volunteer

The overarching goal of the PREVENT Program is to develop a Griffithsin (GRFT) rectal gel that could be used prior to receptive anal intercourse (RAI) to reduce the risk of HIV infection by men who have sex with men (MSM). Project 3 will conduct a randomized, placebo-controlled pre-Phase 1 human study to measure GRFT safety, pharmacokinetics (PK) and pharmacodynamics (PD). We will recruit 18 healthy men to participate in a prospective trial to evaluate GRFT carbopol gel versus a matched placebo in a 2:1 randomization design. The study will address traditional product safety and PK parameters, but we will also evaluate the effect of the product on adaptive immunity to GRFT by conducting a three stage study. The first stage will involve a single drug exposure. In Stages 2 and 3, men will receive 5 doses of gel product on consecutive days separated by a two week washout period. Rectal biopsies and other samples taken at baseline and during Stages 1-3 will be used to characterize mucosal responses to GRFT including enumeration of HIV target cells and detection of representative HIV receptors and epithelial junction proteins in the rectumby immunohistochemistry and flow cytometry. The biopsies will also be used for a PD assessment by ex vivo challenge of the tissue with HIV-1. Additionally, we will employ a systems biology approach, including transcriptomics, proteomics and microbiome analysis, to analyze the global impact of GRFT treatment on the mucosal environment in the rectum.

预防计划的首要目标是发展格里菲辛(GRFT)直肠 可在接受性肛交(RAI)前使用的凝胶，可降低感染艾滋病毒的风险 男男性行为者(MSM)感染。项目3将进行随机、 测量GRFT安全性的安慰剂对照前期1期人体研究， 药代动力学(PK)和药效学(PD)。我们将招募18名健康男性 参与一项前瞻性试验，以评估GRFT卡波姆凝胶与匹配的 安慰剂采用2：1随机设计。这项研究将解决传统产品安全问题。 和PK参数，但我们也会评估产品对自适应的影响 通过进行三个阶段的研究获得对GRFT的免疫力。第一阶段将涉及一个单一的 接触毒品。在第二阶段和第三阶段，男性将获得5剂凝胶产品 连续几天由两周的冲洗期隔开。直肠活组织检查和其他 在基线和阶段1-3期间采集的样本将被用来表征粘膜 对GRFT的反应，包括对艾滋病毒目标细胞的计数和对 直肠中具有代表性的HIV受体和上皮连接蛋白 免疫组织化学和流式细胞术。活组织检查也将用于PD 用HIV-1对组织进行体外挑战进行评估。此外，我们将聘请一名 系统生物学方法，包括转录组学、蛋白质组学和微生物组学 分析，分析GRFT治疗对粘膜环境的整体影响 在直肠里。