A randomized clinical trial of early empiric anti-Mycobacterium tuberculosis therapy for sepsis in sub-Saharan Africa

撒哈拉以南非洲地区早期经验性抗结核杆菌治疗败血症的随机临床试验

基本信息

批准号：
10443820
负责人：
Scott K Heysell
金额：
$ 65.78万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-18 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443820
关键词：
Achievement Admission activity Adult Adverse drug event Africa Africa South of the Sahara Antibiotics Antitubercular Agents Area Blood Cessation of life Clinical Clinical Microbiology Clinical Trials Communities Critical Illness Diagnosis Diagnostic tests Dose Drug Kinetics Early treatment Etiology Functional disorder Goals HIV HIV-2 HIV/TB Health Priorities Hospital Mortality Hospitalization Immune response Infection Karnofsky Performance Status Knowledge Lead Life Measures Mycobacterium tuberculosis Odds Ratio Organ Participant Patients Persons Pharmaceutical Preparations Pharmacodynamics Phase Polymerase Chain Reaction Randomized Randomized Clinical Trials Regimen Rifampin Risk Reduction Sample Size Sepsis Serum Side Site Sputum Syndrome Tanzania Temperature Testing Time Tuberculosis Tuberculosis diagnosis Uganda Undifferentiated Vulnerable Populations Weight World Health Organization antimicrobial base clinical trial participant design early phase clinical trial global health improved isoniazid lipoarabinomannan microbial mortality open label point-of-care diagnostics primary endpoint prospective secondary endpoint septic patients standard care standard of care tuberculosis drugs tuberculosis treatment urinary

项目摘要

PROJECT SUMMARY/ABSTRACT Sepsis is a syndrome of critical illness defined as life-threatening organ dysfunction due to a dysregulated host response to infection and is a leading cause of global mortality. In May of 2017, the World Health Organization (WHO) made sepsis a global health priority. Yet, little is known about sepsis in the global South and specifically sub-Saharan Africa where there are at least 1.2-2.2 million cases of sepsis and 6.5 million deaths due to infection annually. The majority of these patients are living with HIV. We have determined the leading cause of sepsis in this region is tuberculosis (TB) which is responsible for 25-30% of bloodstream infections in septic patients. TB sepsis is associated with 20-50% mortality rates with the majority of deaths occurring within the first 4-5 days of admission. However, it is difficult to identify TB sepsis clinically or with diagnostic tests which are often unavailable and have limited sensitivity. Therefore, TB can be missed and patients with TB sepsis may not receive anti-TB therapy, or if they do, it may be delayed. However, we have found that empiric treatment of TB in septic patients without a confirmed diagnosis of TB improves 28 day survival. We have also studied anti-TB pharmacokinetics/pharmacodynamics in septic patients and discovered considerably low circulating drug concentrations that are suboptimal for microbial kill. Therefore, our hypotheses are that immediate anti-TB therapy will improve 28 day survival compared to anti-TB therapy that is administered only after a diagnosis is made, and that optimized sepsis-specific dosing will improve 28 day mortality compared to conventional WHO recommended weight-based dosing regardless of the timing of administration. We will test these hypotheses through a randomized 2x2 factorial clinical trial where participants with HIV and sepsis will be randomized to 1) empiric immediate initiation of anti-TB therapy plus standard care or diagnosis dependent anti-TB therapy and standard care and 2) sepsis-specific dose anti-TB therapy plus standard care or conventional WHO weight-based recommended dose anti-TB therapy and standard care. This randomized 2x2 factorial clinical trial is strongly endorsed by Tanzanian and Ugandan community advisory boards and will be the first to determine the optimal content, dosing, and timing of the antimicrobial regimen for adult sepsis in sub-Saharan Africa.

项目概要/摘要脓毒症是一种危重疾病综合征，定义为由于宿主失调而导致危及生命的器官功能障碍对感染的反应是全球死亡的主要原因。 2017 年 5 月，世界卫生组织组织（世界卫生组织）将脓毒症列为全球健康优先事项。然而，全球对脓毒症知之甚少南部非洲，特别是撒哈拉以南非洲地区，至少有 1.2-220 万败血症病例，6.5 每年有数百万人因感染死亡。这些患者中的大多数都感染了艾滋病毒。我们已经确定该地区脓毒症的主要原因是结核病 (TB)，它占血液的 25-30% 脓毒症患者的感染。结核败血症与 20-50% 的死亡率相关，其中大部分死亡发生在入院后的前 4-5 天内。然而，临床上或通过诊断很难识别结核败血症。诊断测试通常无法获得且敏感性有限。因此，结核病可能会被漏诊结核败血症患者可能不会接受抗结核治疗，或者即使接受，也可能会被推迟。然而，我们有发现对未确诊结核病的脓毒症患者进行结核病经验治疗可改善 28 天生存。我们还研究了脓毒症患者的抗结核药代动力学/药效学，并发现循环药物浓度相当低，不足以杀死微生物。因此，我们的假设与抗结核治疗相比，立即抗结核治疗将提高 28 天生存率仅在做出诊断后给药，并且优化的脓毒症特异性剂量将在 28 天后得到改善与世界卫生组织推荐的基于体重的传统剂量（无论何时给药）相比，死亡率行政。我们将通过随机 2x2 析因临床试验来检验这些假设，其中患有艾滋病毒和脓毒症的参与者将被随机分配到 1) 立即开始经验性抗结核治疗加上标准护理或诊断依赖的抗结核治疗和标准护理以及 2) 脓毒症特异性抗结核剂量治疗加上标准护理或常规世界卫生组织基于体重的推荐剂量抗结核治疗和标准护理。这项随机 2x2 析因临床试验得到了坦桑尼亚和乌干达的强烈支持社区咨询委员会将第一个确定最佳内容、剂量和时间撒哈拉以南非洲成人脓毒症的抗菌治疗方案。