Clinical trial NCT05178069: LGG Supplementation in Patients With AUD and ALD
Official title: Lactobacillus Rhamnosus GG: A Novel Probiotic Therapy for Treating Alcohol Use Disorder
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Alcohol Use Disorder
Alcohol-associated Liver Disease
Keywords: AUD
ALD
AH
TLFB
LTDH
AUDIT
WHO Drinking Level Reduction Criteria
MELD
ALT
AST
ABIC
Total Bilirubin
Heavy Drinking
Drinking Pattern
AUD Domains
Albumin
Lead sponsor: University of Louisville
Sponsor class: OTHER
Collaborators: name: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
First posted: 2022-01-05
Enrollment: 60
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Time by Treatment
Primary purpose: TREATMENT

Brief summary: 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

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

1. Current (last 12 months) DSM V diagnosis of dependence on any psychoactive substance other than alcohol or nicotine,
2. Positive urine drug screen at baseline for any illegal substance other than marijuana,
3. History of hospitalization for alcohol intoxication delirium, alcohol withdrawal delirium or seizure,
4. Participation in any research study for alcoholism treatment within 3 months prior to signing the informed consent,
5. Pharmacological treatment with naltrexone, acamprosate, topiramate, or disulfiram within 1 month prior to randomization,
6. Lifetime diagnosis based on DSM-V criteria of schizophrenia, bipolar disorder, or other psychosis, eating disorders; current or past year diagnosis of major depression
7. In the investigators' opinion, moderate to severe risk of suicide (e.g., active plan, or recent attempt in last 6 months),
8. Current use of psychotropic medications that cannot be discontinued,
9. Clinically significant medical abnormalities (apart from moderate ALD, MELD≤19),
10. Clinical Institute Withdrawal Assessment for Alcohol revised (CIWA-Ar) \>10, at screening for more than 3 days,
11. 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)
12. History of clinically significant hypotension (e.g., history of lipotimia and/or syncopal episodes)
13. History of adverse reactions to needle puncture,
14. Obesity (BMI ≥ 33.0 kg/m2),
15. Pregnancy; incarceration; inability to provide consent
16. Signs of systemic infection: Fever \> 38o C, positive blood or ascites cultures, on appropriate antibiotic therapy for \> 3 days within 3 days of inclusion
17. Acute gastrointestinal bleeding requiring \> 2 units blood transfusion within the previous 2 weeks
18. Undue risk from immunosuppression: Positive HBsAg; positive skin PPD skin test or history of treatment for tuberculosis; known HIV infection

Primary outcomes:
measure: 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
timeFrame: 180 days
measure: By reducing relapse episodes to minimal/absent incident level
timeFrame: 180 days
measure: By showing a significant positive effect on one or more of the underlying neurobehavioral domains.
timeFrame: 180 days
measure: By lowering a biochemical marker of alcohol intake
timeFrame: 180 days
Secondary outcomes:
measure: By significantly improving liver related and clinical markers
timeFrame: 180 days
measure: By substantially improving the overall health as assessed by the patient reported outcomes
timeFrame: 180 days
measure: By lowering frequency and intensity of treatment/disease based adverse effects (AE).
timeFrame: 180 days
Other outcomes:
measure: To determine the therapeutic-mechanistic markers of gut-brain axis, pro-inflammatory activity in AUD
timeFrame: 180 days
Locations:
city: Louisville
country: United States
facility: University of Louisville Hospital
state: Kentucky
Study officials:
affiliation: Department of Medicine, University of Louisville
name: Vatsalya Vatsalya, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Medicine, University of Louisville
name: Craig J McClain, MD
role: STUDY_CHAIR
affiliation: University of Louisville
name: Harsh Tiwari, MD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.