LGG Supplementation in Patients With AUD and ALD

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Alcohol Use Disorder, Alcohol-associated Liver Disease

Intervention / Treatment
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* Drug: : Placebo for Probiotic
* Dietary Supplement: Lactobacillus Rhamnosus GG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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: 12 ≤ (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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Time by treatment study.
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AUD, ALD, AH, TLFB, LTDH, AUDIT, WHO Drinking Level Reduction Criteria, MELD, ALT, AST, ABIC, Total Bilirubin, Heavy Drinking, Drinking Pattern, AUD Domains, Albumin