LGG Supplementation in Patients With AUD and ALD

Alcohol Use Disorder Clinical Trial

— AUD+ALD  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05178069
• Other study ID #: 21.1038
• Secondary ID: K23AA029198
• Status: Recruiting
• Phase: Phase 2
• Start date: June 1, 2022
• Est. completion date: February 28, 2027

Study information

• Verified date: May 2024
• Source: University of Louisville
• Contact: Theresa Durham, BSN
• Phone: 502-377-4609
• Email: theresa.durham[@]louisville.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: February 28, 2027
• Est. primary completion date: August 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Alcohol Drinking
• Alcohol Use Disorder
• Alcoholism
• Liver Diseases

Intervention

Drug:
• : Placebo for Probiotic
Capsule manufactured without active ingredients.

Dietary Supplement:
• Lactobacillus Rhamnosus GG
Probiotic nutritional supplement; Lactobacillus Rhamnosus G

Locations

Country	Name	City	State
United States	University of Louisville Hospital	Louisville	Kentucky

Sponsors (2)

Lead Sponsor	Collaborator
University of Louisville	National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Country where clinical trial is conducted

United States, 

References & Publications (8)

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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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: IL1ß, IL33, IL18, IL17, IL22, TNFa [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: IL1ß, IL33, IL18, IL17, IL22, TNFa [Units for all: pg/ml].	180 days
Primary	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
Primary	By reducing relapse episodes to minimal/absent incident level	(Unit: incident frequency).	180 days
Primary	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
Primary	By lowering a biochemical marker of alcohol intake	PeTH (Unit: µmol/L)	180 days
Secondary	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
Secondary	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
Secondary	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

External Links

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