Tirzepatide s Dopaminergic Effects in Alcohol Use Disorders (AUD)

Tirzepatide s Dopaminergic Effects in Alcohol Use Disorders (AUD), a Phase 1b Study

Background:

Glucagon-like peptide 1 (GLP-1) agonist drugs are used to treat diabetes and aid weight loss. They may also help reduce cravings for drugs and alcohol. Researchers want to know if a GLP-1 drug (tirzepatide) can lessen the urge to drink in people with alcohol use disorder (AUD).

Objective:

To learn how the brains of people with AUD respond to a GLP-1 drug.

Eligibility:

People aged 21 to 65 years with AUD who are non-treatment seeking. They must be enrolled in protocol 14-AA-0181. Healthy volunteers are also needed.

Design:

This study consists of Part 1 and Part 2.

Part 1 (Imaging Procedures): Five healthy volunteers will undergo 2 to 3 combined positron emission tomography/magnetic resonance imaging (PET/MRI) scans, with an interval of 2 to 3 weeks between scans. For each scan, a radioactive substance (tracer) will be administered intravenously. Participants will undergo PET/MRI scanning to assess brain activity during resting state. Methylphenidate (Ritalin) will be administered during each scan. Each imaging session will last approximately 2 hours. Tirzepatide and placebo will not be administered in Part 1. Participants with alcohol use disorder (AUD) are not included in Part 1. The purpose of this part of the study is to assess test/retest reproducibility of the PET/MRI combined scan measures.

Part 2 (Randomization to Tirzepatide & Placebo): Participants will be randomized to receive either Tirzepatide or Placebo first. Healthy Volunteers and AUD participants will receive both treatments in a crossover design. Tirzepatide and placebo will be administered via subcutaneous injection (under the skin) once weekly for 2 to 3 weeks. This treatment period will be followed by 2 to 3 PET/MRI combined imaging scans described in the next paragraph. After a washout interval of approximately 2 to 3 weeks, participants will cross over to the alternate treatment (tirzepatide or placebo), administered once weekly for 2 to 3 weeks. This second treatment period will be followed by an additional 2 to 3 PET/MRI scans. Participants may receive up to 3 doses of tirzepatide and 3 doses of placebo.

Part 2 (Imaging Procedures): Healthy Volunteers and participants with an AUD will undergo PET/MRI scans at two time points: following tirzepatide administration and following placebo administration. For each scan a radioactive substance (tracer) will be administered intravenously. Brain activity will be measured during PET/MRI acquisition during resting state. Methylphenidate will be administered during 1 of the scans at each time point. Each imaging session will last approximately 2 hours. Participants will wear a device to track their activity for at least 1 week before each set of scans. They will have tests of their thinking, memory, and attention.

Study Description:

Protocol has 2 parts:

Part 1 (n=5 healthy volunteers): Assess the reproducibility of striatal dopamine (DA) measures in response to iv methylphenidate (MP) using PET/MR combined scanning and the bolus infusion protocol in healthy controls.

Part 2 (n=88, 44 healthy volunteers and 44 AUD): Evaluate Tirzepatide s brain dopaminergic effects in controls and participants with alcohol use disorder (AUD) as compared to placebo (2 injections 1 week apart from each other) on MP induced brain DA increases and functional reactivity using PET/fMRI, on dopamine D1 and D2 receptors and reactivity to alcohol and food cues. We hypothesize that Tirzepatide compared to placebo will (1) increase striatal dopamine D2 receptors while decreasing D1 receptors, (2) attenuate DA increases to MP and functional reactivity and (3) blunt the response to alcohol and food cues to a greater extent in AUD than control participants.

Primary Objectives:

Part 1: Reproducibility of striatal DA measures

Part 2: Effects of Tirzepatide on: striatal dopamine D1R and D2R availability; striatal DA increase; brain reactivity to MP and to food and alcohol cues in AUD and in healthy controls.

Secondary Objectives:

Part 1: Subjective responses to MP

Part 2: Examine Tirzepatide s effects on subjective effects to MP, sleep, alcohol craving (AUD only), alcohol withdrawal symptoms (AUD only), food craving, locomotor activity, mood and weight.

Primary Endpoints:

Part 1: Striatal DA changes with MP tested in two separate occasions

Part 2: Striatal D1R and D2R availability; Striatal DA increases with MP; Brain functional reactivity to MP and to alcohol and food cues. Measures collected twice after placebo and after Tirzepatide

Secondary Endpoints:

Self-reports of drug effects (Parts 1 & 2)

Sleep measures: actigraphy and self-reports (Part 2).

Alcohol Craving (only AUD): Desire for Alcohol Questionnaire (DAQ). (Part 2)

Alcohol Withdrawal (only AUD): Clinical Institute Withdrawal Assessment (CIWA) (Part 2)

Food Craving: Food Cravings Questionnaire - State and Trait (FCQ S, FCQ-T) (Part 2)

Locomotor activity: actigraphy (Part 2)

Mood: Profile of Mood States (POMS, Parts 1 & 2)

Exploratory Endpoints:

Part 2:

• Brain structure and function assessed by MRI (task and resting fMRI, structural MRI)
• Cognitive Test Performance
• Weight
• Eating phenotypes

• INCLUSION CRITERIA:

Healthy Volunteer Participants

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

1. Enrollment in 14AA0181.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Male or female, ages 21-65 years old.
4. Ability to understand and willingness to sign a written informed consent document.
5. Have or had any prior experience with stimulant drugs including cocaine, methylphenidate, amphetamine or methamphetamine, or prescription stimulants (prescription or recreational use), whether or not they have had a past substance use disorder.

AUD Participants

To be eligible, individuals with AUD must meet the following criteria:

1. Enrollment in 14AA0181.

2. Stated willingness to comply with all study procedures and availability for the duration of the study.

3. Male or female, ages 21-65 years old.

4. Ability to understand and willingness to sign a written informed consent document.

5. DSM 5 diagnosis of mild to moderate AUD.

6. Have or had any prior experience with stimulant drugs including cocaine, methylphenidate, amphetamine or methamphetamine, or prescription stimulants (prescription or recreational use), whether or not they have had a past substance use disorder.

7. Minimum 2-year history of heavy drinking (SAMSHA s criteria for heavy drinking: for men 5 or more drinks/day on at least 5 different days per month; and for women 4 or more

   drinks/day on at least 5 different days per month.

8. Non treatment seeking AUD participants.

EXCLUSION CRITERIA:

All Participants (Healthy Volunteers and AUD)

1. Presence of ferromagnetic objects in the body that are contraindicated for MRI of the head, fear of enclosed spaces, or other standard contraindication to MRI

2. Cannot lie comfortably flat on his/her back for up to 2 hours in the PET/MRI scanner.

3. BMI <23 or >35 (but no more than 500 lbs). The PET/MRI scanner bed is tested to a weight limit of 500 lbs.

4. Have had previous radiation exposure (from X-rays, PET scans, or other exposure) that, with the exposure from this study, would exceed NIH annual research limits as determined by medical history and physical exam.

5. Pregnant or breast-feeding: Females of childbearing potential, or with tubal ligation, or are post-menopausal and are age 55 or less will undergo a urine pregnancy test and it must be negative to continue participation. Urine pregnancy tests will be repeated on subsequent days of study (i.e., within 24 hours before study procedures). Females must not be currently breastfeeding.

6. Women using oral contraceptives (Part 2 of study). Women of childbearing age who are taking oral contraceptives will be required to switch to a non-oral hormonal contraceptive method (ie implants, injections, or IUDs) or add a barrier method (condoms) for the duration of the study and for 4 weeks after the last dose of study drug after explaining to them that Tirzepatide could make contraceptive less effective. We will not provide nonoral contraceptive medications to participants.

7. Severe head trauma with loss of consciousness > 60 minutes

8. Current severe mental illness (schizophrenia, bipolar disorder).

9. Montgomery-Asberg depression rating scale (MADRS) total score > 35 or suicidal thoughts item score > 3, indicating severe depression or moderate suicidality, respectively.

10. Thyroid cancer or family history of thyroid cancer or personal or family history of multiple endocrine neoplasia syndrome type-2 (MEN-2).

11. History for cerebral aneurysm.

12. Past or present history of chest pain and trouble breathing with activity.

13. History of Heart Disease, Hypertension or Cardiovascular disorders.

14. History of seizures, anxiety, panic attacks, psychosis or glaucoma which are contraindicated with receiving methylphenidate.

15. History of gallbladder disease, pancreatitis, gastroparesis, diabetic retinopathy, acute kidney injury (AKI), as these are contraindicated for Tirzepatide.

16. History of allergic reaction to methylphenidate, Tirzepatide or allergic reactions to dyes or preservatives.

17. Major medical problems that can permanently impact brain function (e.g., seizures, psychosis, stroke, Alzheimer s disease, Parkinson s disease, traumatic brain injury with

    loss of consciousness > 30 minutes, clinically significant arrhythmias except bradycardia, and HIV+).

18. Clinically significant laboratory findings that could impact brain function or study procedures (e.g., active infections, significant EKG results, hepatic or renal failure) will be

    exclusionary.

19. Current DSM-5 diagnosis of a psychiatric disorder that required daily psychoactive medications (antidepressant, antipsychotics, stimulants, opioids, benzodiazepines or barbiturates) in the past two months and that could impact brain function at the time of the study as determined by history and clinical exam.

20. History of moderate or severe SUD (other than nicotine in HV s, and nicotine, cannabis or alcohol for AUD participants).

21. Daily current use (past 2 months) of the following drugs/medications are exclusionary: stimulant or stimulant-like drugs or medications (cocaine, methamphetamine, amphetamine, methylphenidate, modafinil); opioid drugs or medications; other GLP-1 or anti-diabetic drugs (e.g., insulin, sulfonylureas) medications, antianginal agents; antiarrhythmics; systemic corticosteroids; anticholinergics; anticoagulants; anticonvulsants; antidepressants with dopaminergic effects (bupropion, sertraline, and dopamine agonists like pramipexole and ropinirole); beta-blocker antihypertensives; antineoplastics; antipsychotics; anxiolytics (benzodiazepine or barbiturates); or lithium. Note that alcohol and cannabis use are not exclusionary but participants cannot be intoxicated on the day of study as evidence of alcohol in breathalyzer or cannabis in saliva. Caffeine and nicotine are permitted but participants will be asked to refrain from consuming caffeine or nicotine products (including cigarettes) two hours prior to the study. Antihistamines are also not exclusionary but should not be used on the day of study.

22. *Non-English speakers (must also be able to read and comprehend English

    • We are excluding non-English speakers since the study includes questionnaires that are validated for English and only some are available in Spanish. The fMRI paradigms also require that the subject be able to speak, read and comprehend English.

Note that subjects will not be excluded from enrollment onto this study if their urine test or breath alcohol level (BAL) is positive for alcohol/drugs on initial screening. The following guidelines will be followed for positive drug/alcohol screens on study procedure days involving imaging scans and neuropsychological testing for all participants:

• If a subject s breath alcohol (>0.08%) screen test is positive on days involving imaging (PET/MRI) and NP testing, the procedures will be postponed and rescheduled. We will allow for up to 3 rescheduled study days resulting from positive breath alcohol screens. If subject continues to show up intoxicated they will be withdrawn.
• If urine drug screen is positive for THC-COOH a saliva drug screen will be performed and subject may proceed with study day testing procedures if saliva results for THC are negative. If we are unable to perform the saliva drug screen for any reason, the study day procedures will be postponed. If the urine/saliva drug test is positive on the third rescheduled visit, the participant will be withdrawn from the study. Saliva THC is not required for determining eligibility.
• If a participants urine drug screen test is positive for cocaine, heroin or methamphetamine after 3 days of rescheduling they will be excluded.