LGG Supplementation in Patients With AUD and ALD (AUD+ALD)

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

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

Study Overview

• Status: Recruiting
• Conditions: Alcohol Use Disorder; Alcohol-associated Liver Disease
• Intervention / Treatment: Drug: : Placebo for Probiotic; Dietary supplement: Lactobacillus Rhamnosus GG

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.

• Study Type: Interventional
• Enrollment (Anticipated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Steve Mahanes; Phone Number: 502-852-1388; Email: steve.mahanes@louisville.edu
• Study Contact Backup: Name: Suman K Jha, MBBS; Phone Number: 773-997-5461; Email: sumankumar.jha@louisville.edu

Study Locations

• United States
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Recruiting
      • University of Louisville Hospital
      • Contact: Vatsalya Vatsalya, MD, PgD, MSc, MS, FRSM; Phone Number: 502-952-8928; Email: v0vats01@louisville.edu
      • Contact: Steve Mahanes; Phone Number: 5028521388; Email: steve.mahanes@louisville.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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: 12 ≤ (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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Comparator: Placebo for Probiotic; Placebo capsule that matches the probiotic capsule in appearance will be given once daily for 180 days.	Drug: : Placebo for Probiotic; Capsule manufactured without active ingredients.; Other Names: Dummy capsule
Active Comparator: Active Comparator: Lactobacillus Rhamnosus GG; Dietary supplement capsule (Lactobacillus Rhamnosus GG) will be given once daily for 180 days.	Dietary supplement: Lactobacillus Rhamnosus GG; Probiotic nutritional supplement; Lactobacillus Rhamnosus G; Other Names: Culturelle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Timeline Followback for past 180 days [Unit: numerical frequency], AUDIT [Unit: numerical frequency], monthly drinking questionnaire [Unit: numerical frequency]).	180 days
By reducing relapse episodes to minimal/absent incident level	(Unit: incident frequency).	180 days
By showing a significant positive effect on one or more of the underlying neurobehavioral domains.	Questionnaires: reward (reasons for heavy drinking questionnaire or RHDQ [Unit: numerical frequency]), craving (Penn Alcohol Craving Scale or PACS, [Unit: numerical frequency]; and obsessive compulsive drinking scale or OCDS [Unit: numerical frequency]), withdrawal (Clinical Institute Withdrawal Assessment Alcohol Scale Revised [CIWA-AR] or CIWA-AR [Unit: numerical frequency]), and reinforcement effects (Desires for Alcohol Questionnaire or DAQ [Unit: numerical frequency]).	180 days
By lowering a biochemical marker of alcohol intake	PeTH (Unit: μmol/L)	180 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
By significantly improving liver related and clinical markers	Liver markers: Aspartate transaminases or AST (Unit: IU/L), Alanine Transaminases or ALT (Unit: IU/L), Albumin (Unit: g/dL), Total bilirubin (Unit: mg/dL), Creatinine (Unit: mg/dL), and INR (Unit: numerical), AST:ALT ratio (numerical unit), Prothrombin Time or PT (Unit: seconds). Clinical marker: Model For End-Stage Liver Disease or MELD ([=0.957 × ln(Cr) + 0.378 × ln(bilirubin) + 1.120 × ln(INR) + 0.643]. Unit: numerical), Maddrey's Discriminant Function for Alcoholic Hepatitis or Maddrey DF ([=4.6 * (Pt's PT - Control PT) + TBili]. Unit: numerical). Laboratory markers: K18M65 and K18M30 (Unit for both: IU/L).	180 days
By substantially improving the overall health as assessed by the patient reported outcomes	Quality of Life or QOL scale [Unit: numerical frequency], Drinker inventory of consequences or DrInC [unit: numerical frequency].	180 days
By lowering frequency and intensity of treatment/disease based adverse effects (AE).	Incident frequency of AE [Unit: numerical], Severity Scale (AE/SAE (Unit: 1-5).	180 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the therapeutic-mechanistic markers of gut-brain axis, pro-inflammatory activity in AUD	By identifying the blood biomarkers of gut-barrier dysfunction and endotoxemia as assessed by: LPS [Unit: EU/ml], LBP [Unit: ng/ml], sCD14 [Unit: x 10^6 pg/ml]. Serum Inflammation markers: IL1β, IL33, IL18, IL17, IL22, TNFα [Units for all: pg/ml].; 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): Gamma Aminobutyric Acid or GABA [Unit: pmoles/ml], hexyl-2-methyl butyrate or HMBA (Unit: mmol/L), serotonin (Unit: ng/mL), dopamine (Unit: ng/ml), acetylcholine (Unit: nmol/L), tryptophan (Unit: umol/L), and short-chain fatty acids (Unit: mmol/L). Units can be relative in intensity (as fold-change).; By validating the efficacy of LGG treatment vs. placebo to lower inflammation using an ex-vivo design: Candidate WBC type derived Inflammation markers: IL1β, IL33, IL18, IL17, IL22, TNFα [Units for all: pg/ml].	180 days

Collaborators and Investigators

• Sponsor: University of Louisville
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Investigators: Principal Investigator: Vatsalya Vatsalya, MD PhD, Department of Medicine, University of Louisville; Study Chair: Craig J McClain, MD, Department of Medicine, University of Louisville; Study Director: Evan J. Winrich, M.D., Department of Medicine, University of Louisville

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• Details of the Study at NIH Reporter
• Clinical Laboratory for the Intervention Development of AUD and Organ-Injury

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2022
• Primary Completion (Anticipated): August 31, 2026
• Study Completion (Anticipated): February 28, 2027

Study Registration Dates

• First Submitted: November 9, 2021
• First Submitted That Met QC Criteria: December 15, 2021
• First Posted (Actual): January 5, 2022

Study Record Updates

• Last Update Posted (Actual): May 12, 2023
• Last Update Submitted That Met QC Criteria: May 11, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Heavy Drinking; ALT; Albumin; ALD; MELD; AUD; AST; AH; TLFB; LTDH; AUDIT; WHO Drinking Level Reduction Criteria; ABIC; Total Bilirubin; Drinking Pattern; AUD Domains
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Digestive System Diseases; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Liver Diseases; Alcohol Drinking; Alcoholism
• Other Study ID Numbers: 21.1038; K23AA029198 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data is shared through NIMH NDA portfolio
• IPD Sharing Time Frame: 2028 -2030 year
• IPD Sharing Access Criteria: Application to NIAAA for getting the dataset

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No