Tirzepatide for people with metabolic alcohol-associated liver disease and alcohol use disorder

A Randomized, Double-Blind, Placebo-Controlled, Flexible Dose Phase 2 Study of Efficacy and Safety of Tirzepatide in Individuals With Alcohol Use Disorder and Metabolic Alcohol-associated Liver Disease

This trial will test whether the weight-loss drug tirzepatide can help adults with alcohol use disorder and metabolic alcohol-associated liver disease reduce drinking, lose weight, and lower liver fat.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 120 (estimated)
• Ages: 21 Years to 100 Years
• Sex: All
• Sponsor: National Institutes of Health Clinical Center (CC) (NIH)
• Locations: 1 site (Bethesda, Maryland)
• Trial ID: NCT07046819 on ClinicalTrials.gov

What this trial studies

This Phase 2, randomized, placebo-controlled interventional trial will give subcutaneous tirzepatide or placebo to adults with AUD and MetALD and monitor safety and efficacy. Participants undergo screening and baseline assessments including physical exam, blood and urine tests, cardiac testing, Fibroscan for liver steatosis and stiffness, alcohol use questionnaires, and optional brain and liver imaging, with key tests repeated at follow-up visits. The co-primary endpoints are percent body weight reduction and percent reduction in liver steatosis measured by Fibroscan CAP, and secondary outcomes include MRI spectroscopy, biomarkers of liver injury and inflammation, drinking behavior measures, neuropsychiatric outcomes, epigenetic and brain metabolite measures, and safety. All study dosing and most assessments occur in person at the clinical center with scheduled clinic visits for follow-up.

Who should consider this trial

Good fit: Adults aged 21 or older with diagnosed alcohol use disorder, current drinking above threshold (>14 drinks/week for men, >7 for women), Fibroscan CAP >240 indicating liver steatosis, and BMI 25 to <40 kg/m^2 who can provide consent and attend clinic visits are ideal candidates.

Not a fit: People without liver steatosis, with BMI outside the 25–<40 range, who are pregnant or breastfeeding, who have contraindications to tirzepatide, or who cannot attend in-person visits are unlikely to qualify or benefit from this trial.

Why it matters

Potential benefit: If successful, tirzepatide could reduce alcohol consumption, promote weight loss, and decrease liver fat, which may lower the risk of liver-related complications in people with AUD and MetALD.

How similar studies have performed: Tirzepatide and other GLP-1/GIP agonists have demonstrated substantial weight loss and metabolic liver benefits in prior studies and there are preliminary data suggesting effects on drinking behavior, but using tirzepatide specifically for AUD with MetALD is a novel application.

Eligibility criteria

* INCLUSION CRITERIA

To be eligible to participate in this study, an individual must meet all of the following criteria:

1. Age 21 or older
2. Ability to provide written informed consent
3. Females: Negative urine pregnancy test, not currently breastfeeding, agree to abstain or use accepted form of contraception including use of oral contraceptives and an additional barrier method of contraceptive such as condoms; use of an approved IUD or other longacting reversible contraceptive (LARC); have a male sexual partner who is surgically sterilized; or have exclusively female sexual partner(s)
4. Males: Agree to abstain or use accepted form of contraception, such as condoms.
5. Diagnosis of AUD as confirmed by MINI
6. Current alcohol use as assessed via the TLFB (\>14 standard drinks per week for males and \>7 standard drinks per week for females on average for the last 8 weeks)
7. Liver steatosis as determined by Fibroscan (CAP score \>240) at screening
8. BMI \>= 25 and \<40 kg/m\^2
9. metALD as defined by at least one out of 5 criteria at screening:

   1. BMI \>= 25 and \<40 kg/m\^2
   2. Fasting serum glucose \>= 5.6mmol/L \[100mg/dL\] or HbA1c \>=5.7%
   3. Blood pressure \>=130/85 or specific antihypertensive drug treatment
   4. Plasma triglycerides \>=1.70mmol/L \[150mg/dL\] or lipid lowering treatment
   5. Plasma HDL-cholesterol less than 1.0mmol/L \[40mg/dL\] or lipid lowering treatment

EXCLUSION CRITERIA

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Treatment seeking for alcohol use disorder
2. History of a serious hypersensitivity reaction to GLP-1RA/GIPRA
3. Current/past use of GLP-1RA/GIPRA within the last 3 months
4. Clinically significant and/or unstable cardiovascular disease over the past 12 months
5. History of diabetes mellitus or blood hemoglobin A1c (HbA1c) \>= 6.5 % at screening
6. Any underlying clinically significant and/or unstable acute or chronic liver disease unrelated to alcohol use at screening, history of cirrhosis, esophageal varices
7. Subjects with platelets count of less than 110,000/ mm\^3
8. Alanine aminotransferase or aspartate aminotransferase exceeding 5 times the upper limit of normal levels at screening
9. Bilirubin 2x UNL or Creatinine \> 2 mg/dL at screening
10. Patients with coagulopathy defined as INR \>1.5, prothrombin time prolonged by \> 3s, and/or platelets \<75,000 / mm\^3 at screening
11. Positive HIV test or positive Hepatitis B surface antigen (HBsAg), and/or positive Hepatitis C antibody (HCV) at screening
12. Chronic renal failure as estimated by glomerular filtration rate (GFR) \< 60mL/min/1.73 m\^2 at screening
13. History of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
14. History of previous bariatric surgery or transplant surgery
15. Patients with significant hematologic abnormalities, as defined by hemoglobin \< 8g/dL and/or white blood count \<1500 cells/microL
16. Current or prior history of any clinically significant disease, including, seizure disorder, epilepsy, alcohol related seizures within 12 months of screening, uncontrolled endocrine disease, hemorrhagic stroke, cancer within the past 5 years or any other significant abnormality identified at the time of screening that, in the judgment of the investigator or study clinician, would preclude safe completion of the study
17. Use of any medications that interfere with tirzepatide
18. Use of the following medications with glucose lowering properties in the last 30 days: GLP-1RA, GLP-1RA/GIPRA, insulin, metformin, sulfonylurea, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors
19. Use of the following medications: Any medication that requires intramuscular administration injections. Systemic corticosteroids
20. Use of any investigational drugs within 1 month, or five half-lives, whichever is longer, of the study procedures
21. Presence of any current suicidality or a lifetime history of suicide attempt or suicidal ideation within the past year
22. History of serious mental illnesses including psychotic disorders, bipolar disorders, severe anxiety, mood, or trauma-related disorders and other psychiatric conditions which in the opinion of the investigators would impede the patient's participation or compliance in the study
23. History of liver decompensation events such as hepatic encephalopathy or ascites
24. History of severe gastroparesis
25. History of pancreatitis in the last 5 years or if subject has chronic pancreatitis

For optional MRI: a) Presence of ferromagnetic objects in the body that may be adversely affected by or contraindicated for MRI, fear of enclosed spaces, or other standard contraindication to MRI, as determined by self-report b) Use of MRI- incompatible intrauterine device (IUD).

Individuals who are pregnant or breastfeeding, or with severe hepatic or renal liver impairment will be excluded from this study because there is no clinical data on the safety of tirzepatide in these populations, including the impact on the fetus or infant. To assess pregnancy status, participants who can become pregnant will be required to take a urine pregnancy test and to test negative before administering study drug.

Where this trial is running

Bethesda, Maryland

• National Institutes of Health Clinical Center — Bethesda, Maryland, United States (Recruiting)

Study contacts

• Principal investigator: Falk W Lohoff, M.D. — National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Study coordinator: Nada M Saleh

Conditions Metabolic Alcohol-associated Liver Disease; Alcohol Use Disorder; BMI; Weight; Alcohol; Metabolism