PRESCIENT: A phase IIc, open-label, randomized controlled trial of ultra-short course bedaquiline, clofazimine, pyrazinamide and delamanid versus standard therapy for drug-susceptible tuberculosis
PRESCIENT:一项针对药物敏感结核病的超短疗程贝达喹啉、氯法齐明、吡嗪酰胺和德拉马尼与标准疗法的 IIc 期、开放标签、随机对照试验
基本信息
- 批准号:10488329
- 负责人:
- 金额:$ 122.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-07 至 2026-04-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdultAdverse eventAftercareArtificial IntelligenceCharacteristicsClinicalClinical DataClinical TrialsConfidence IntervalsCountryData CollectionDoseDrug CombinationsDrug ExposureDrug InteractionsDrug KineticsDrug resistanceEnsureEvaluationFrequenciesFutureGoalsGuidelinesHIVHIV SeropositivityHIV/TBHaitiHepatitisInbred BALB C MiceIndividualInfrastructureLaboratory ProceduresLiquid substanceLungMeasuresMethodsMicrobiologyMinimum Inhibitory Concentration measurementMonitorMusOutcomeParticipantPatientsPharmaceutical PreparationsPhasePhenotypePopulationPredispositionProbabilityProcessPyrazinamideRandomizedRandomized Controlled TrialsRegimenRelapseResistanceRifampinRifamycinsSafetySample SizeSkinSouth AfricaSurfaceTestingTimeTranslatingTranslationsTreatment FailureTreatment ProtocolsTuberculosisWidthWorld Health Organizationadverse event monitoringantiretroviral therapybactericidebaseclinical practiceclinical research sitedesigndrug standarddrug-sensitiveefficacy trialexperimental studyfollow-upgenome sequencinghazardhigh throughput screeningmouse modelmycobacterialnovelopen labelpatient populationpharmacokinetic modelpre-clinicalpreclinical evaluationresearch clinical testingresistance frequencyresistance mutationresponserisk sharingsafety assessmentstandard caretreatment adherencetreatment armtreatment durationtreatment responsetuberculosis drugstuberculosis treatmentwhole genome
项目摘要
PROJECT SUMMARY/ABSTRACT
Standard first-line therapy for drug-susceptible tuberculosis (DS-TB) is highly effective but complicated by long
treatment duration and rifamycin drug-drug interactions, particularly with antiretroviral therapy (ART) in high HIV-
TB burden countries. A well-tolerated and efficacious rifamycin-free regimen that can shorten TB treatment
duration is critically needed to achieve World Health Organization (WHO) targets towards ending TB. Our group
pioneered the use of an artificial-intelligence-enabled parabolic response surface (PRS) platform allowing rapid
identification of the most effective drug-dose combinations by testing only a small fraction of the total drug-dose
efficacy response surface. This approach determined that drug combinations including bedaquiline (BDQ),
clofazimine (CFZ), and pyrazinamide (PZA) at optimal dose ratios were more effective than standard DS-TB
treatment, achieving relapse-free cure in mouse models within 3-4 weeks. Adding delamanid (DLM) as a 4th drug
was equivalent in potency, achieving 100% relapse-free cure in only 3 weeks. This is substantially shorter than
time to relapse-free cure in mouse studies supporting other TB treatment shortening trials. Bactericidal and
sterilizing ability confirmed in other experiments, and favorable intra-lesional pharmacokinetics (PK), provides
additional justification for evaluation of the BDQ-CFZ-PZA-DLM (BCZD) combination for treatment shortening.
This 8-week rifamycin-free ultrashort regimen fulfills key requirements of the WHO target regimen profile for DS-
TB: lower potential for drug-drug interactions, established tolerability and safety, constituent agents registered
and accessible, and optimized dosing based on clinical data. We hypothesize that BCZD will demonstrate
superior microbiologic efficacy relative to standard therapy during the first 8 weeks of treatment for patients with
DS-TB. To test this, we shall conduct a Phase IIc, open-label, randomized controlled trial to investigate the
efficacy and safety of an 8-week regimen of BCZD, paving the way for a definitive treatment-shortening trial and
potentially shifting clinical practice. Our trial, called PRESCIENT, will randomize 156 adults with smear-positive
DS-TB, with and without HIV, to receive BCZD for 8 weeks versus standard therapy for 26 weeks (1:1 ratio). The
primary objective is a superiority efficacy comparison of time to liquid culture conversion through 8 weeks; the
Phase IIc design also enables evaluation of clinical endpoints through extended post-treatment follow up to 56
weeks (Aim 1a - efficacy). Secondary objectives include rigorous assessment of safety and tolerability (Aim 1b
- safety), and drug susceptibility testing and whole genome sequencing to determine frequency of treatment-
emergent resistance to BCZD (Aim 1c - resistance). We shall also explore the effect of experimental drug
exposure, derived from population PK models, on time to culture positivity as a measure of mycobacterial burden
and treatment response, and on corrected QT interval (Aim 2 - PK/PD). PRESCIENT will be conducted at
established clinical research sites in Haiti and South Africa which have access to large populations of patients
with DS-TB and have the necessary expertise and infrastructure to successfully implement this project.
项目总结/摘要
药物敏感性结核病(DS-TB)的标准一线治疗非常有效,但由于长期使用,
治疗持续时间和利福霉素药物相互作用,特别是在艾滋病毒感染率高的患者中与抗逆转录病毒治疗(ART)的相互作用,
结核病负担国家。一种耐受性良好且有效的无利福霉素方案,可缩短结核病治疗时间
为实现世界卫生组织(世卫组织)消灭结核病的目标,我们集团
率先使用人工智能抛物线响应面(PRS)平台,
通过仅测试总药物剂量的一小部分来鉴定最有效的药物剂量组合
功效响应面这种方法确定了包括贝达喹啉(BDQ)在内的药物组合,
氯法齐明(CFZ)和吡嗪酰胺(PZA)在最佳剂量比下比标准DS-TB更有效
治疗,在3-4周内在小鼠模型中实现无复发治愈。添加delamanid(DLM)作为第4种药物
在效力上相当,仅在3周内实现100%无复发治愈。这大大短于
小鼠研究中的无复发治愈时间,支持其他结核病治疗缩短试验。杀菌和
在其他实验中证实的杀菌能力和有利的病灶内药代动力学(PK),
评价BDQ-CFZ-PZA-DLM(BCZD)复方制剂缩短治疗时间的其他依据。
这一8周无利福霉素超短方案符合DS的WHO目标方案特征的关键要求-
TB:药物间相互作用的可能性较低,已确定耐受性和安全性,已注册的成分药物
并且基于临床数据优化给药。我们假设BCZD将证明
在治疗的前8周内,
DS-TB为了验证这一点,我们将进行一项IIc期、开放标签、随机对照试验,
为期8周的BCZD治疗方案的有效性和安全性,为确定性治疗缩短试验铺平了道路,
可能会改变临床实践。我们的试验名为PRESCIENT,将随机抽取156名涂片阳性的成年人,
DS-TB,有和没有HIV,接受BCZD 8周与标准治疗26周(1:1比例)。的
主要目的是比较8周内液体培养转化时间的优效性;
IIc期设计还可以通过延长治疗后随访至56例来评价临床终点
周(目标1a -疗效)。次要目标包括严格评估安全性和耐受性(目标1b
- 安全性),以及药物敏感性测试和全基因组测序,以确定治疗频率-
对BCZD的紧急抗性(Aim 1c -抗性)。我们还将探讨实验药物的作用
暴露量,来源于群体PK模型,至培养阳性时间作为分枝杆菌负荷的指标
和治疗反应,以及校正的QT间期(目标2 - PK/PD)。PRESCIENT将在
在海地和南非建立了临床研究中心,可以接触到大量患者
与DS-TB合作,并拥有成功实施该项目所需的专业知识和基础设施。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
SERENA Patricia KOENIG其他文献
SERENA Patricia KOENIG的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('SERENA Patricia KOENIG', 18)}}的其他基金
PRESCIENT: A phase IIc, open-label, randomized controlled trial of ultra-short course bedaquiline, clofazimine, pyrazinamide and delamanid versus standard therapy for drug-susceptible tuberculosis
PRESCIENT:一项针对药物敏感结核病的超短疗程贝达喹啉、氯法齐明、吡嗪酰胺和德拉马尼与标准疗法的 IIc 期、开放标签、随机对照试验
- 批准号:
10661811 - 财政年份:2022
- 资助金额:
$ 122.1万 - 项目类别:
Same-Day HIV Testing and Treatment Initiation to Improve Retention in Care
当日艾滋病毒检测和治疗启动,以提高护理保留率
- 批准号:
8623097 - 财政年份:2013
- 资助金额:
$ 122.1万 - 项目类别:
Same-Day HIV Testing and Treatment Initiation to Improve Retention in Care
当日艾滋病毒检测和治疗启动,以提高护理保留率
- 批准号:
8540744 - 财政年份:2013
- 资助金额:
$ 122.1万 - 项目类别:
Health Outcomes/Cost of Early vs Delayed ART in Haiti
海地早期 ART 与延迟 ART 的健康结果/成本
- 批准号:
7110292 - 财政年份:2004
- 资助金额:
$ 122.1万 - 项目类别:
Health Outcomes/Cost of Early vs Delayed ART in Haiti
海地早期 ART 与延迟 ART 的健康结果/成本
- 批准号:
7286030 - 财政年份:2004
- 资助金额:
$ 122.1万 - 项目类别:
Cost-effectiveness of Early vs. Delayed Antiretroviral Therapy in Haiti
海地早期抗逆转录病毒治疗与延迟抗逆转录病毒治疗的成本效益
- 批准号:
7761257 - 财政年份:2004
- 资助金额:
$ 122.1万 - 项目类别:
Cost-effectiveness of Early vs. Delayed Antiretroviral Therapy in Haiti
海地早期抗逆转录病毒治疗与延迟抗逆转录病毒治疗的成本效益
- 批准号:
7558017 - 财政年份:2004
- 资助金额:
$ 122.1万 - 项目类别:
Cost-effectiveness of Early vs. Delayed Antiretroviral Therapy in Haiti
海地早期抗逆转录病毒治疗与延迟抗逆转录病毒治疗的成本效益
- 批准号:
8018138 - 财政年份:2004
- 资助金额:
$ 122.1万 - 项目类别:
Health Outcomes/Cost of Early vs Delayed ART in Haiti
海地早期 ART 与延迟 ART 的健康结果/成本
- 批准号:
6952012 - 财政年份:2004
- 资助金额:
$ 122.1万 - 项目类别:
Health Outcomes/Cost of Early vs Delayed ART in Haiti
海地早期 ART 与延迟 ART 的健康结果/成本
- 批准号:
6863052 - 财政年份:2004
- 资助金额:
$ 122.1万 - 项目类别:
相似海外基金
Co-designing a lifestyle, stop-vaping intervention for ex-smoking, adult vapers (CLOVER study)
为戒烟的成年电子烟使用者共同设计生活方式、戒烟干预措施(CLOVER 研究)
- 批准号:
MR/Z503605/1 - 财政年份:2024
- 资助金额:
$ 122.1万 - 项目类别:
Research Grant
Early Life Antecedents Predicting Adult Daily Affective Reactivity to Stress
早期生活经历预测成人对压力的日常情感反应
- 批准号:
2336167 - 财政年份:2024
- 资助金额:
$ 122.1万 - 项目类别:
Standard Grant
RAPID: Affective Mechanisms of Adjustment in Diverse Emerging Adult Student Communities Before, During, and Beyond the COVID-19 Pandemic
RAPID:COVID-19 大流行之前、期间和之后不同新兴成人学生社区的情感调整机制
- 批准号:
2402691 - 财政年份:2024
- 资助金额:
$ 122.1万 - 项目类别:
Standard Grant
Elucidation of Adult Newt Cells Regulating the ZRS enhancer during Limb Regeneration
阐明成体蝾螈细胞在肢体再生过程中调节 ZRS 增强子
- 批准号:
24K12150 - 财政年份:2024
- 资助金额:
$ 122.1万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Migrant Youth and the Sociolegal Construction of Child and Adult Categories
流动青年与儿童和成人类别的社会法律建构
- 批准号:
2341428 - 财政年份:2024
- 资助金额:
$ 122.1万 - 项目类别:
Standard Grant
Understanding how platelets mediate new neuron formation in the adult brain
了解血小板如何介导成人大脑中新神经元的形成
- 批准号:
DE240100561 - 财政年份:2024
- 资助金额:
$ 122.1万 - 项目类别:
Discovery Early Career Researcher Award
RUI: Evaluation of Neurotrophic-Like properties of Spaetzle-Toll Signaling in the Developing and Adult Cricket CNS
RUI:评估发育中和成年蟋蟀中枢神经系统中 Spaetzle-Toll 信号传导的神经营养样特性
- 批准号:
2230829 - 财政年份:2023
- 资助金额:
$ 122.1万 - 项目类别:
Standard Grant
Usefulness of a question prompt sheet for onco-fertility in adolescent and young adult patients under 25 years old.
问题提示表对于 25 岁以下青少年和年轻成年患者的肿瘤生育力的有用性。
- 批准号:
23K09542 - 财政年份:2023
- 资助金额:
$ 122.1万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of new specific molecules associated with right ventricular dysfunction in adult patients with congenital heart disease
鉴定与成年先天性心脏病患者右心室功能障碍相关的新特异性分子
- 批准号:
23K07552 - 财政年份:2023
- 资助金额:
$ 122.1万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Issue identifications and model developments in transitional care for patients with adult congenital heart disease.
成人先天性心脏病患者过渡护理的问题识别和模型开发。
- 批准号:
23K07559 - 财政年份:2023
- 资助金额:
$ 122.1万 - 项目类别:
Grant-in-Aid for Scientific Research (C)