LGG Supplementation in Patients With AUD and ALD

Официальное название

Lactobacillus Rhamnosus GG: A Novel Probiotic Therapy for Treating Alcohol Use Disorder

Обзор

To test the efficacy of 6-month LGG compared to placebo in treating Alcoholic Use Disorder (AUD) and liver injury in Alcoholic Hepatitis (AH). And to evaluate the effects of LGG treatment compared to placebo on therapeutic-mechanistic markers of the gut-brain axis and pro-inflammatory activity in patients with AUD and moderate AH

Подробное описание

Aim. 1: To test the efficacy of 6-month LGG compared to placebo in treating AUD: (1a) by lowering heavy drinking (1b) by reducing relapse episodes to minimal/absent incident level; (1c) by showing a significant positive effect on one or more of the underlying neurobehavioral domain, and (1d) by lowering a biochemical marker of alcohol intake.

Aim. 2: To test if 6-month LGG treatment compared to placebo will improve the symptoms and liver injury in AH: (2a) by significantly improving liver related tests (AST, ALT, AST:ALT, albumin, bilirubin and INR; K18M65 and K18M30) and clinical severity/prognostic markers (MELD, Maddrey); (2b) by substantially improving the overall health as assessed by the patient reported outcomes (Quality of Life \[QOL\] scale, and drinker inventory of consequences \[DrInC\]); and (2c) by lowering frequency and intensity of treatment/disease based adverse effects (AE).

Aim. 3: To evaluate the effects of LGG treatment compared to placebo on therapeutic-mechanistic markers of gut-brain axis and pro-inflammatory activity in patients with AUD and moderate AH: (3a) by identifying the blood biomarkers of gut-barrier dysfunction and endotoxemia, and inflammation; (3b) by determining the therapeutic targets of LGG involved in the gut-brain axis of AUD using LC-MS metabolomic fecal assays (candidate markers of gut-dysfunction associated neurotransmitters); and (3c) by validating the efficacy of LGG treatment vs. placebo to lower inflammation using an ex-vivo design.

Вмешательства

• Препарат : Placebo for Probiotic
  Capsule manufactured without active ingredients.
• Пищевая добавка Lactobacillus Rhamnosus GG
  Probiotic nutritional supplement; Lactobacillus Rhamnosus G

Первичные конечные точки

• By lowering heavy drinking to meet the criteria on the responder definitions of abstinence, no heavy drinking days, WHO 1-level, and WHO 2-level reduction [Срок оценки: 180 days]
• By reducing relapse episodes to minimal/absent incident level [Срок оценки: 180 days]
• By showing a significant positive effect on one or more of the underlying neurobehavioral domains. [Срок оценки: 180 days]
• By lowering a biochemical marker of alcohol intake [Срок оценки: 180 days]

Вторичные конечные точки (3)

• By significantly improving liver related and clinical markers [Срок оценки: 180 days]
• By substantially improving the overall health as assessed by the patient reported outcomes [Срок оценки: 180 days]
• By lowering frequency and intensity of treatment/disease based adverse effects (AE). [Срок оценки: 180 days]

Критерии участия

Критерии включения

• Breath alcohol concentration (BAC) equal to 0.00 when the participant signs the informed consent document.
• Age between 21 and 65 years old (inclusive).
• Willingness to receive trial treatment.
• Ability to provide informed consent
• Understanding that this is not an alcohol treatment study.
• Heavy drinking. Men must consume ≥ 20 and women ≥ 14 standardized alcoholic beverages a week for the past 3 months.
• Diagnosis of Alcohol Use Disorder using DSM V criteria.
• 50 <AST<400 U/L; AST > ALT; and ALT < 200 U/L; total bilirubin > 1.2 mg/dL
• Model for End-Stage Liver Disease: 8 ≤ (MELD) ≤19.
• Good health as confirmed by medical history, physical examination, ECG, laboratory tests and vital signs except for liver injury and AUD related history.
• Provide contact information for someone who may be able to contact the subject in case of a missed appointment.
• . Females of child-bearing potential must not be pregnant and must be using birth control

Критерии исключения

• Current (last 12 months) DSM V diagnosis of dependence on any psychoactive substance other than alcohol or nicotine,
• Positive urine drug screen at baseline for any illegal substance other than marijuana,
• History of hospitalization for alcohol intoxication delirium, alcohol withdrawal delirium or seizure,
• Participation in any research study for alcoholism treatment within 3 months prior to signing the informed consent,
• Pharmacological treatment with naltrexone, acamprosate, topiramate, or disulfiram within 1 month prior to randomization,
• Lifetime diagnosis based on DSM-V criteria of schizophrenia, bipolar disorder, or other psychosis, eating disorders; current or past year diagnosis of major depression
• In the investigators' opinion, moderate to severe risk of suicide (e.g., active plan, or recent attempt in last 6 months),
• Current use of psychotropic medications that cannot be discontinued,
• Clinically significant medical abnormalities (apart from moderate ALD, MELD≤19),
• Clinical Institute Withdrawal Assessment for Alcohol revised (CIWA-Ar) >10, at screening for more than 3 days,
• Serious medical diseases, such as cancer, liver cirrhosis, pancreatitis, severe alcohol associated hepatitis, heart chronic failure, chronic kidney failure, chronic intestinal diseases (e.g., Crohn's disease), chronic neurological disorders (e.g., tardive dyskinesia, epilepsy, Parkinson's disease)
• History of clinically significant hypotension (e.g., history of lipotimia and/or syncopal episodes)
• History of adverse reactions to needle puncture,
• Obesity (BMI ≥ 33.0 kg/m2),
• Pregnancy; incarceration; inability to provide consent
• Signs of systemic infection: Fever > 38o C, positive blood or ascites cultures, on appropriate antibiotic therapy for > 3 days within 3 days of inclusion
• Acute gastrointestinal bleeding requiring > 2 units blood transfusion within the previous 2 weeks
• Undue risk from immunosuppression: Positive HBsAg; positive skin PPD skin test or history of treatment for tuberculosis; known HIV infection

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Тройное слепое

Основная цель

Лечение

Центры проведения

США · 1 центр

• University of Louisville Hospital — Louisville

Публикации

• McClain CJ, Vatsalya V, Mitchell MC. Keratin-18: Diagnostic, Prognostic, and Theragnostic for Alcohol-Associated Hepatitis. Am J Gastroenterol. 2021 Jan 1;116(1):77-79. doi: 10.14309/ajg.0000000000001042. PMID 33306505
• Gala KS, Vatsalya V. Emerging Noninvasive Biomarkers, and Medical Management Strategies for Alcoholic Hepatitis: Present Understanding and Scope. Cells. 2020 Feb 25;9(3):524. doi: 10.3390/cells9030524. PMID 32106390
• Vatsalya V, Cave MC, Kong M, Gobejishvili L, Falkner KC, Craycroft J, Mitchell M, Szabo G, McCullough A, Dasarathy S, Radaeva S, Barton B, McClain CJ. Keratin 18 Is a Diagnostic and Prognostic Factor for Acute Alcoholic Hepatitis. Clin Gastroenterol Hepatol. 2020 Aug;18(9):2046-2054. doi: 10.1016/j.cgh.2019.11.050. Epub 2019 Dec 4. PMID 31811953
• Zhou Y, Vatsalya V, Gobejishvili L, Lamont RJ, McClain CJ, Feng W. Porphyromonas gingivalis as a Possible Risk Factor in the Development/Severity of Acute Alcoholic Hepatitis. Hepatol Commun. 2018 Dec 14;3(2):293-304. doi: 10.1002/hep4.1296. eCollection 2019 Feb. PMID 30766965
• Gowin JL, Sloan ME, Stangl BL, Vatsalya V, Ramchandani VA. Vulnerability for Alcohol Use Disorder and Rate of Alcohol Consumption. Am J Psychiatry. 2017 Nov 1;174(11):1094-1101. doi: 10.1176/appi.ajp.2017.16101180. Epub 2017 Aug 4. PMID 28774194
• Vatsalya V, Gowin JL, Schwandt ML, Momenan R, Coe MA, Cooke ME, Hommer DW, Bartlett S, Heilig M, Ramchandani VA. Effects of Varenicline on Neural Correlates of Alcohol Salience in Heavy Drinkers. Int J Neuropsychopharmacol. 2015 Jul 25;18(12):pyv068. doi: 10.1093/ijnp/pyv068. PMID 26209857
• Vatsalya V, Gala KS, Hassan AZ, Frimodig J, Kong M, Sinha N, Schwandt ML. Characterization of Early-Stage Alcoholic Liver Disease with Hyperhomocysteinemia and Gut Dysfunction and Associated Immune Response in Alcohol Use Disorder Patients. Biomedicines. 2020 Dec 24;9(1):7. doi: 10.3390/biomedicines9010007. PMID 33374263
• Vatsalya V, Kong M, Marsano LM, Kurlawala Z, Chandras KV, Schwandt ML, Ramchandani VA, McClain CJ. Interaction of Heavy Drinking Patterns and Depression Severity Predicts Efficacy of Quetiapine Fumarate XR in Lowering Alcohol Intake in Alcohol Use Disorder Patients. Subst Abuse. 2020 Sep 9;14:1178221820955185. doi: 10.1177/1178221820955185. eCollection 2020. PMID 32963470

Идентификаторы

NCT: NCT05178069 · 21.1038 · K23AA029198

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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