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：
10265511
负责人：
Scott K Heysell
金额：
$ 66.28万
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/10265511
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 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 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.

项目摘要/摘要败血症是危害疾病的综合症，被定义为威胁生命的器官功能障碍，导致宿主失调对感染的反应，是全球死亡率的主要原因。 2017年5月，世界卫生组织（WHO）将败血症作为全球健康优先事项。然而，关于全球败血症知之甚少南部，特别是撒哈拉以南非洲，至少有1.2-220万例败血症和6.5例每年因感染而导致的百万人死亡。这些患者中的大多数患有艾滋病毒。我们已经确定该区域败血症的主要原因是结核病（TB），造成25-30％的血液化粪池患者的感染。结核病败血症与20-50％的死亡率有关发生在入院的前4-5天内。但是，很难在临床上或与诊断测试通常不可用，灵敏度有限。因此，可以错过结核结核病患者可能无法接受抗TB疗法，或者如果这样做，可能会延迟。但是，我们有发现未经确定诊断为结核病的化粪池患者对结核病的经验治疗可改善28天生存。我们还研究了化粪池患者的抗TB药代动力学/药效学微生物杀死的循环药物浓度相当低。因此，我们的假设是，与抗TB治疗相比，立即进行抗TB治疗将改善28天的生存率仅在进行诊断后才给予，并且优化的败血症特定给药将改善28天与传统的死亡率相比，他建议基于体重的给药行政。我们将通过随机的2x2阶乘临床试验来检验这些假设，其中艾滋病毒和败血症的参与者将随机分为1）抗TB治疗的经验直接开始标准护理或诊断依赖性抗TB治疗和标准护理以及2）败血症特异性剂量抗TB 治疗加标准护理或常规的人，基于体重建议的剂量抗结核治疗和标准护理。这项随机2x2阶乘临床试验得到坦桑尼亚和乌干达的强烈认可社区咨询委员会，将是第一个确定最佳内容，剂量和时机的人撒哈拉以南非洲成年败血症的抗菌治疗方案。