Phase II trial of tesamorelin for cognition in aging HIV-infected persons

 描述：HIV相关神经认知障碍(HAND)影响30-50%的HIV+患者，包括那些接受联合抗逆转录病毒治疗(CART)的病毒学抑制患者，并且在老年人中不成比例地常见。艾滋病毒的神经认知障碍不仅本身是残疾的来源，而且还因为它通过干扰个人有效实施个人和治疗性补偿策略的能力放大了其他艾滋病毒相关非艾滋病(HANA)条件造成的障碍。尽管如此，目前还没有有效的治疗方法。在这里，我们建议通过结合一种新的生物医学治疗方法--Tesamorelin和一种最先进的行为干预--双向短信来解决这一需求，以最大限度地坚持研究药物。我们的初步数据表明，腹型肥胖(内脏肥胖的标志)、全身炎症和免疫激活与手密切相关。生物医学治疗将是一项随机、双掩蔽、安慰剂对照的替他莫瑞林(TES)II期临床试验，TES是一种GHRH类似物，可减少内脏肥胖、炎症和免疫激活。TES还被证明能增加IGF-1，IGF-1促进脑血管生成、轴突生长和突触形成。纳入标准将是HIV+，年龄40-70岁，在稳定的购物车上至少12周，病毒载量检测不到，有腹部肥胖和可能可逆的手。排除的对象将是根据已发表的研究诊断标准(Antinori等人，2007年)不符合手部标准的个人，以及患有糖尿病或丙型肝炎合并感染的人。共有140名受试者将在加州大学圣迭戈分校和南加州大学以3：2的随机比例(替他莫瑞林：安慰剂)登记，以实现106名受试者完成9个月治疗的可评估样本。我们假设替他莫瑞林将改善通过全球缺陷评分方法测量的神经认知功能的主要结果。我们还将评估继发性机制的结果如下：1)炎症和单核细胞激活的生物标志物，2)脑磁共振波谱(MRS)证据大脑炎症和3)MRI海马体体积增加。将使用多种工具来提高这一受损人群的依从性并与治疗疲劳作斗争，包括一种最先进的行为干预，包括对个性化的 为遵守建设(ITab)平台发送短信。参与研究的其他激励措施将包括提供手机和短信数据计划，向完成盲目安慰剂对照阶段的所有参与者提供开放标签的积极研究药物延期，以及补偿参与者的时间和费用。通过优化神经认知功能，我们努力减轻购物车上老年艾滋病毒感染者的残疾负担。这项第二阶段试验的成功完成将导致规模更大、持续时间更长的第三阶段研究，以证明疗效。

 DESCRIPTION: HIV-associated neurocognitive disorders (HAND) affect 30-50% of HIV+ individuals, including those with virologic suppression on combination antiretroviral therapy (cART), and are disproportionately common in older individuals. Neurocognitive impairment in HIV is a source of disability not only in itself, but also because it magnifies impediments due to other HIV-associated non-AIDS (HANA) conditions by interfering with individuals' abilities to effectively implement personal and therapeutic compensatory strategies. Despite this, there is currently no effective treatment. Here we propose to address this need by combining a novel biomedical treatment, tesamorelin, and a state-of-the-art behavioral intervention, 2-way texting, to maximize adherence to study drug. Our preliminary data indicate that abdominal obesity (a marker of visceral adiposity), systemic inflammation, and immune activation are closely linked to HAND. The biomedical treatment will be a randomized, double-masked, placebo-controlled phase II clinical trial of tesamorelin (Tes), a GHRH analogue that reduces visceral adiposity, inflammation and immune activation. Tes has also been shown to increase IGF-1, which promotes brain angiogenesis, neurite outgrowth and synaptogenesis. Inclusion criteria will be HIV+, aged 40-70 years on stable cART for at least 12 weeks with undetectable viral load, with abdominal obesity and potentially reversible HAND. Exclusions will be individuals not meeting criteria for HAND based on published research diagnostic criteria (Antinori et al, 2007) as well as those with diabetes mellitus or hepatitis C coinfection. A total of 140 subjects will be enrolle at UCSD and USC and randomized 3:2 (tesamorelin:placebo) to achieve an evaluable sample of 106 subjects completing treatment for 9 months. We hypothesize that tesamorelin will improve the primary outcome of neurocognitive performance as measured by the global deficit score method. We will also evaluate secondary mechanistic outcomes as follows: 1) biomarkers of inflammation and monocyte activation, 2) brain magnetic resonance spectroscopy (MRS) evidence of cerebral inflammation and 3) MRI hippocampal volume increases. Multiple tools will be used to enhance adherence and combat treatment fatigue in this impaired population, including a state-of-the-art behavioral intervention comprising an adaptation of the individualized Texting for Adherence Building (iTAB) platform. Additional incentives to study participation will be provision of cell phones and data plans for text messaging, an open-label active study drug extension offered to all participants who complete the blinded placebo-controlled phase, and reimbursement for participant time and expense. By optimizing neurocognitive function, we endeavor to reduce the burden of disability in aging HIV-infected individuals on cART. Successful completion of this Phase II trial will lead to larger and longer duration Phase III studies to demonstrate efficacy.