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/文摘
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)
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SERENA Patricia KOENIG其他文献
SERENA Patricia KOENIG的其他文献
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{{ 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:
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