Fecal microbiota transplant for Alcohol-Associated Cirrhosis
粪便微生物群移植治疗酒精相关性肝硬化
基本信息
- 批准号:10444624
- 负责人:
- 金额:$ 54.85万
- 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:2022-09-12 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AbstinenceAffectAlcohol consumptionAlcohol-Induced DisordersAlcoholic HepatitisAlcoholsAminobutyric AcidsAntibioticsAntimicrobial ResistanceBile AcidsBiologicalBrainCirrhosisClinicalClinical TrialsClostridium difficileCognitionCognitiveCognitive TherapyDevelopmentDiseaseDouble-Blind MethodEncapsulatedEngraftmentEnrollmentFDA approvedFecesFormulationFreeze DryingFunctional disorderGlutamatesGoalsHepatic EncephalopathyInfectionInfrastructureLinkLiquid substanceLiverLiver CirrhosisLiver DysfunctionLiver diseasesMeasuresMediator of activation proteinMedicineMicrobeMinorityMolecularMonitorMorbidity - disease rateOralOrganOutcomeParticipantPatient Outcomes AssessmentsPatientsPatternPharmaceutical PreparationsPhasePlacebo ControlPlacebosPlasmaPopulationPreparationProbioticsPrognosisPsychometricsPublishingRandomizedRandomized Clinical TrialsRecurrenceSafetySerumServicesSickness Impact ProfileSocioeconomic StatusStandardizationStructureTestingTherapeuticUnderserved PopulationVolatile Fatty Acidsalcohol cravingalcohol use disorderbasebehavioral pharmacologybrain dysfunctioncapsulecognitive functioncognitive testingcomparativecravingdisorder preventiondouble-blind placebo controlled trialenema administrationevidence baseexperiencefecal transplantationgamma-Aminobutyric Acidgut dysbiosisgut microbesgut microbiotagut-brain axishealth related quality of lifeimprovedinstrumentliver functionliver injuryliver transplantationmetabolomicsmicrobialmicrobial communitymicrobial compositionmicrobiotamortalitynovel strategiesprimary outcomepsychologicpsychosocialrandomized placebo-controlled clinical trialrandomized trialsafety outcomessuccesstherapeutic targettrial designurinary
项目摘要
Current medication options for AUD have only partial success and have a low evidence base in cirrhosis. Gut
dysbiosis, which may be initiated by alcohol, contributes to cirrhosis development. Our overarching goal is to
develop a potent therapeutic targeting the intestinal microbiota to alleviate the impact of AUD and AROD
through the gut-liver-brain axis. We base our approach on fecal microbiota transplant (FMT), originally
developed for recurrent Clostridioides difficile infection (rCDI). We have also shown in randomized, placebo-
controlled clinical trials the benefit and safety of different FMT formulations in cirrhosis. Furthermore, in a
recent randomized trial of actively drinking AUD cirrhotic patients, we demonstrated that FMT reduced alcohol
consumption and craving, and improved cognition and psychosocial health-related quality of life (HRQOL)
versus placebo. We also found similar engraftment with capsule versus enema FMT. The FDA regulates FMT
as a drug and a biologic. Our group uses Good Manufacturing Practices to manufacture FMT products in both
liquid and freeze-dried, encapsulated formulations.
Our hypothesis is that restructuring the gut microbiota using FMT will reduce alcohol consumption
compared to placebo in patients with AUD and cirrhosis. To test this, we will conduct a Phase 1b/2a
double-blind, placebo-controlled, randomized clinical trial using administration of a standardized oral
encapsulated FMT preparation (FMT) at baseline and day 30 in patients with AUD and cirrhosis.
Aim 1: Measure the effect of FMT on alcohol consumption. The primary outcome is number of abstinent days
at three months in FMT compared to placebo. We will assess daily alcohol consumption and cravings using
patient-reported measures and objective urinary and plasma markers.
Aim 2: Determine the impact of FMT on safety and liver dysfunction. We will monitor safety outcomes and liver
function throughout the trial.
Aim 3: Determine the impact of FMT on microbial compositional and function. Comparative analyses of stool
microbial composition, and serum metabolomics will be performed between and within groups. Targeted
metabolomics will be focused on neuroactive metabolites that are produced or modulated by microbiota, e.g.,
SCFA, γ-aminobutyric acid (GABA), glutamate, indolic compounds, and bile acids.
Aim 4: Determine the impact of FMT on brain dysfunction and patient-reported outcomes using cognitive
testing and HRQOL testing. We will evaluate HRQOL and cognition using validated instruments (Sickness
Impact Profile, EncephalApp Stroop, Psychometric Hepatic Encephalopathy Score).
We will enroll 80 participants with AUD cirrhosis (randomized 1:1 to FMT versus placebo) under FDA IND. The
team has access to patients, microbial expertise, infrastructure and AUD trial experience to carry out the trial.
目前AUD的药物选择仅部分成功,并且在肝硬化中的证据基础较低。肠道
可能由酒精引发的生态失调有助于肝硬化的发展。我们的首要目标是
开发针对肠道微生物群的有效治疗药物,以减轻AUD和AROD的影响
穿过肠-肝-脑轴我们的方法基于粪便微生物群移植(FMT),最初
开发用于复发性艰难梭菌感染(rCDI)。我们还在随机的安慰剂中显示-
对照临床试验的好处和安全性不同FMT配方在肝硬化。此外,在A
最近对主动饮酒的AUD糖尿病患者进行的随机试验表明,FMT可以减少酒精
消费和渴望,改善认知和心理健康相关的生活质量(HRQOL)
对比安慰剂。我们还发现胶囊与灌肠FMT的植入相似。FDA监管FMT
作为药物和生物制剂。我们集团采用良好的生产规范,在两个生产基地生产FMT产品。
液体和冷冻干燥的包封制剂。
我们的假设是,使用FMT重组肠道微生物群将减少酒精消费
在AUD和肝硬化患者中与安慰剂相比。为了测试这一点,我们将进行第1b/2a阶段
一项使用标准化口服给药的双盲、安慰剂对照、随机临床试验
在患有AUD和肝硬化的患者中在基线和第30天的封装的FMT制剂(FMT)。
目的1:测量FMT对酒精消耗的影响。主要结果是禁欲天数
与安慰剂组相比,FMT组三个月时。我们将评估每日饮酒量和渴望使用
患者报告的测量值和客观的尿液和血浆标记物。
目的2:确定FMT对安全性和肝功能障碍的影响。我们将监测安全性结果和肝脏
在整个审判过程中发挥作用。
目的3:确定FMT对微生物组成和功能的影响。粪便比较分析
微生物组成和血清代谢组学将在组间和组内进行。针对性
代谢组学将集中于由微生物群产生或调节的神经活性代谢物,例如,
SCFA、γ-氨基丁酸(GABA)、谷氨酸、吲哚化合物和胆汁酸。
目的4:确定FMT对脑功能障碍和患者报告的结果的影响,
测试和HRQOL测试。我们将使用经过验证的工具(疾病)评估HRQOL和认知
影响特征,脑卒中Stroop评分,心理测量学肝性脑病评分)。
我们将在FDA IND下招募80名患有AUD肝硬化的参与者(1:1随机分配至FMT组与安慰剂组)。
团队可以接触患者、微生物专业知识、基础设施和AUD试验经验来进行试验。
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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Jasmohan S Bajaj其他文献
WED-383 - Serum ammonia levels do not correlate with overt hepatic encephalopathy severity and time to resolution in hospitalized patients with cirrhosis
- DOI:
10.1016/s0168-8278(23)00853-x - 发表时间:
2023-06-01 - 期刊:
- 影响因子:
- 作者:
Jasmohan S Bajaj;Nikolaos T. Pyrsopoulos;Robert Rahimi;Zeev Heimanson;Christopher Allen;Robert Israel;Don Rockey - 通讯作者:
Don Rockey
THU494 - Serum metabolites on admission associate with the development of nosocomial infections in inpatients with cirrhosis
THU494 - 入院时的血清代谢物与肝硬化住院患者医院感染的发生发展相关
- DOI:
10.1016/s0168-8278(22)01041-8 - 发表时间:
2022-07-01 - 期刊:
- 影响因子:33.000
- 作者:
Jasmohan S Bajaj;Jacqueline O’Leary;Puneeta Tandon;Guadalupe Garcia-Tsao;Patrick S. Kamath;Paul J. Thuluvath;Ram Subramanian;Hugo E. Vargas;Sara McGeorge;Andrew Fagan;Florence Wong;Jennifer Lai;Leroy Thacker;Rajender Reddy - 通讯作者:
Rajender Reddy
THU023 - Active alcohol misuse is linked with lower short-chain fatty acid producing microbiota in a matched study of 450 patients with cirrhosis
THU023 - 在一项针对 450 例肝硬化患者的配对研究中,积极的酒精滥用与短链脂肪酸产生微生物群减少有关
- DOI:
10.1016/s0168-8278(22)00643-2 - 发表时间:
2022-07-01 - 期刊:
- 影响因子:33.000
- 作者:
Jasmohan S Bajaj;Amirhossein Shamsaddini;Masoumeh Sikaroodi;Brian Davis;Puneet Puri;Michael Fuchs;Andrew Fagan;Sara McGeorge;Patrick Gillevet - 通讯作者:
Patrick Gillevet
FRI-546 - Nosocomial infections in cirrhosis are unpredictable and vary based on region of the world: CLEARED study
- DOI:
10.1016/s0168-8278(23)00733-x - 发表时间:
2023-06-01 - 期刊:
- 影响因子:
- 作者:
Jasmohan S Bajaj;Florence Wong;Qing Xie;Patrick S. Kamath;Mark Topazian;Shiv Kumar Sarin;Shiva Kumar;Sebastián Marciano;Fiona Tudehope;Robert Gibson;Adam Doyle;Stephen Riordan;Alberto Queiroz Farias;Nabiha Faisal;Puneeta Tandon;Marie Jeanne Lohoues;Carlos Benitez;Yongchao Xian;Chuanwu Zhu;Minghua Su - 通讯作者:
Minghua Su
SAT496 - SBP vs. non-SBP bacterial infections at admission have comparable outcomes in a multi-center cohort of inpatients with cirrhosis
在一项多中心肝硬化住院患者队列中,入院时 SAT496 - SBP 与非 SBP 细菌感染的结局相当
- DOI:
10.1016/s0168-8278(22)02066-9 - 发表时间:
2022-07-01 - 期刊:
- 影响因子:33.000
- 作者:
Jacqueline O’Leary;K.Rajende Reddy;Puneeta Tandon;Patrick S. Kamath;Guadalupe Garcia-Tsao;Flornce Wong;Jennifer C Lai;Ram Subramanian;Paul J. Thuluvath;Benedict Maliakkal;Hugo E. Vargas;Scott Biggins;Leroy Thacker;Jasmohan S Bajaj - 通讯作者:
Jasmohan S Bajaj
Jasmohan S Bajaj的其他文献
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{{ truncateString('Jasmohan S Bajaj', 18)}}的其他基金
Fecal microbiota transplant for Alcohol-Associated Cirrhosis
粪便微生物群移植治疗酒精相关性肝硬化
- 批准号:
10703378 - 财政年份:2022
- 资助金额:
$ 54.85万 - 项目类别:
BCCMA: Targeting Gut Microbiome in Gastrointestinal and Liver Diseases in US Veterans; CMA4: At the Crossroads of the Gut Microbiome, Cirrhosis, and PTSD
BCCMA:针对美国退伍军人胃肠道和肝脏疾病中的肠道微生物组;
- 批准号:
10475994 - 财政年份:2022
- 资助金额:
$ 54.85万 - 项目类别:
Liver Cirrhosis Network: Clinical Research Centers
肝硬化网络:临床研究中心
- 批准号:
10487561 - 财政年份:2021
- 资助金额:
$ 54.85万 - 项目类别:
Liver Cirrhosis Network: Clinical Research Centers
肝硬化网络:临床研究中心
- 批准号:
10700058 - 财政年份:2021
- 资助金额:
$ 54.85万 - 项目类别:
Liver Cirrhosis Network: Clinical Research Centers
肝硬化网络:临床研究中心
- 批准号:
10308126 - 财政年份:2021
- 资助金额:
$ 54.85万 - 项目类别:
Gut Microbiota in the Modulation of Outcomes after Liver Transplant
肠道微生物群对肝移植后结果的调节
- 批准号:
10231248 - 财政年份:2020
- 资助金额:
$ 54.85万 - 项目类别:
Gut Microbiota in the Modulation of Outcomes after Liver Transplant
肠道微生物群对肝移植后结果的调节
- 批准号:
10054215 - 财政年份:2020
- 资助金额:
$ 54.85万 - 项目类别:
Health IT generated PROs to Improve Outcomes in Cirrhosis
健康 IT 生成 PRO 来改善肝硬化的治疗结果
- 批准号:
10374779 - 财政年份:2018
- 资助金额:
$ 54.85万 - 项目类别:
Modulation of Gut-Brain Axis Using Fecal Microbiome Transplant Capsules in Cirrhosis
使用粪便微生物移植胶囊调节肝硬化的肠脑轴
- 批准号:
9335590 - 财政年份:2017
- 资助金额:
$ 54.85万 - 项目类别:
Bile Acids and Gut Microbiome in the Pathogenesis of Inflammation in Cirrhosis
胆汁酸和肠道微生物组在肝硬化炎症发病机制中的作用
- 批准号:
8994662 - 财政年份:2015
- 资助金额:
$ 54.85万 - 项目类别:
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