LGG Supplementation in Patients With AUD and ALD

Phase 2

Recruiting

• Conditions: Alcohol-associated Liver Disease; Alcohol Use Disorder
• Interventions: Dietary Supplement: Lactobacillus Rhamnosus GG

• Registration Number: NCT05178069
• Lead Sponsor: University of Louisville

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.

Study Timeline

• Study First Submitted: 2021-11-09
• Study First Submitted QC: 2021-12-15
• Study First Posted: 2022-01-05
• Study Start: 2022-06-01
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-03
• Last Update Posted: 2024-12-06
• Primary Completion: 2026-08-31
• Study Completion: 2027-02-28

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Active Comparator: Lactobacillus Rhamnosus GG	Lactobacillus Rhamnosus GG	Dietary supplement capsule (Lactobacillus Rhamnosus GG) will be given once daily for 180 days.

Primary Outcome Measures

Name	Time	Method
By lowering a biochemical marker of alcohol intake	180 days	PeTH (Unit: μmol/L)
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	180 days	Timeline Followback for past 180 days \[Unit: numerical frequency\], AUDIT \[Unit: numerical frequency\], monthly drinking questionnaire \[Unit: numerical frequency\]).
By showing a significant positive effect on one or more of the underlying neurobehavioral domains.	180 days	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 \[Unit: numerical frequency\]).
By reducing relapse episodes to minimal/absent incident level	180 days	(Unit: incident frequency).

Secondary Outcome Measures

Name	Time	Method
By lowering frequency and intensity of treatment/disease based adverse effects (AE).	180 days	Incident frequency of AE \[Unit: numerical\], Severity Scale (AE/SAE (Unit: 1-5).
By significantly improving liver related and clinical markers	180 days	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).
By substantially improving the overall health as assessed by the patient reported outcomes	180 days	Quality of Life or QOL scale \[Unit: numerical frequency\], Drinker inventory of consequences or DrInC \[unit: numerical frequency\].

Trial Locations

Locations (1)

University of Louisville Hospital; 🇺🇸 Louisville, Kentucky, United States