Ketogenic Diet (KD) in Alcoholism

• ClinicalTrials.gov Identifier: NCT03255031
• Recruitment Status: Recruiting
• First Posted: August 21, 2017
• Last Update Posted: February 10, 2023
• Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) )

Tracking Information

• First Submitted Date: August 18, 2017
• First Posted Date: August 21, 2017
• Last Update Posted Date: February 10, 2023
• Actual Study Start Date: October 24, 2017
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 9, 2022)

Assessment of ketogenic diet [ Time Frame: end of study ]

To assess the effects of a ketogenic diet in alcoholic patients hospitalized for the treatment of alcohol detoxification, on: (1) withdrawal symptoms, which will be measured using the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar), as well as with the quantification of medications required to control withdrawal symptoms (benzodiazepines); (2) brain functions as assessed by fMRI (rest and activation), (3) MRS and (4) structural MRI. We will complete studies in 50 alcoholics (25 given a ketogenic diet and 25 a regular diet).

Original Primary Outcome Measures (submitted: August 18, 2017)

• To assess ketogenic diet on withdrawal ratings (CIWA) and Benzodiazepine use during withdrawal in the first week of detoxification. [ Time Frame: 3 years ]
• To assess ketogenic diet on brain function (during rest and activation assessed with fMRI), neurochemistry (assessed with MRS) and structure (assessed with MRI). [ Time Frame: 3 years ]
• To assess ketogenic diet on NP performance. [ Time Frame: 3 years ]

Current Secondary Outcome Measures (submitted: February 28, 2020)

To assess the effects of a ketogenic diet in alcohol use disorder (AUD) subjects. [ Time Frame: end of study ]

Determination of ketogenic diet on improved mood, sleep, and alcohol craving.

• Original Secondary Outcome Measures (submitted: August 18, 2017): To determine if ketogenic diet improves: 1. sleep. 2. mood. 3. alcohol craving. [ Time Frame: 3 years ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Ketogenic Diet (KD) in Alcoholism
• Official Title: Ketogenic Diet (KD) in Alcoholism

Brief Summary

Background:

A ketogenic diet (KD) is high in fat and low in carbohydrates. Research has shown that a KD can lessen tremor in animals withdrawing from alcohol. KD can also help people who have difficulties with thinking, sleep, and mood. Researchers want to see if KD can lessen symptoms of alcohol withdrawal in people with alcohol use disorder.

Objective:<TAB>

To test the effects of a ketogenic diet on alcohol withdrawal symptoms.

Eligibility:

Adults 18 years or older who are moderate or severe alcohol drinkers and are seeking treatment for alcohol use. They must be in the NIAAA inpatient alcohol treatment program.

Design:

Participants will be screened under another protocol. They will have a medical and psychiatric history, physical exam, and blood and urine tests. Participants will have a breath test for alcohol.

The study will be done in a 3-week stay in the clinic.

Participants will get either a KD or Standard American diet.

Participants will have breathalyzer, blood, and urine tests.

Participants will have magnetic resonance imaging (MRI) scans. The scanner is a cylinder in a magnetic field. They will lie on a table that slides in and out of the cylinder. They will do tasks on a computer during the scan.

Participants will have tests of thinking, memory, and attention.

Participants will have their sleeping and waking measured. They will wear a device like a headband held in place with elastic straps. Several electrodes will be placed on the body.

Participants will have heart tests.

Participants will wear an activity monitor on the wrist.

After the clinic stay, participants will be called by phone about 5 times over 3 months.

...

Detailed Description

Alcohol intoxication leads to marked reductions in brain glucose metabolism that reflect in part the use of ketones (including acetate) as alternative energy sources by the brain during intoxication. With repeated alcohol exposure both clinical and preclinical studies have shown a shift of brain substrate preference towards ketones. This has led us to question the potential value of a ketogenic diet in alcohol detoxification in order to prevent the ketone deprivation that would follow alcohol detoxification in alcoholics.

Objectives: Here we propose a blinded randomized design to assess the effects of a ketogenic diet on symptoms of alcohol withdrawal and on brain function in alcoholics undergoing inpatient treatment of alcohol detoxification. We hypothesize that a ketogenic diet will increase acetate levels in brain resulting in improved brain function in alcoholics as well as a reduction of alcohol withdrawal symptoms during detoxification.

Study population: Participants diagnosed with alcohol use disorder (AUD) as per DSM IV or DSM 5. Males and females ages 18 years and older will be included.

Design: This will include an inpatient component and outpatient follow-up. Patients are admitted to the Clinical Center (CC) for detoxification, where they undergo treatment as usual (TAU) and will be randomized into a regular versus a ketogenic diet. Patients will be given benzodiazepines only if withdrawal symptoms emerge while receiving either the ketogenic or the regular diet. Within 2-6 days after admission, all patients will undergo an MRI (brain structure and function, functional connectivity and spectroscopy, i.e. MRS) and a battery of neuropsychological tests (NP). MRI scans will also be obtained in week 2. After 3 weeks of inpatient care the MRI scans and NP studies will be repeated. We will complete all study procedures in n=25 patients with AUD with the ketogenic diet and n=25 with the regular diet.

Outcome parameters: Main outcome: To assess the effects of a ketogenic diet in patients hospitalized for the treatment of alcohol detoxification, on: (1) withdrawal symptoms including the need of medications to control them (benzodiazepines); (2) brain function as assessed by fMRI (at rest and during task conditions), (3) MRS, and (4) structural MRI. Secondary Outcomes: To assess the effects of a ketogenic diet on performance of cognitive tests, sleep, mood and craving.

• Study Type: Interventional
• Study Phase: Early Phase 1
• Study Design: Allocation: Randomized; Intervention Model: Single Group Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Basic Science
• Condition: Alcoholism

Intervention

Other: 1. Ketogenic Diet (KD) / Standard American (SA) Meals and Shakes

1. Ketogenic Diet (KD) / Standard American (SA) Meals and Shakes: Participants will be randomized to a meal plan of either a ketogenic diet (KD) or standard American (SA) diet at the time they sign the consent (day 1 or 2 of admission). For each meal at breakfast, lunch and dinner, the diets will consist of SA meal (carbohydrate rich) or KD meal depending on treatment randomization. Compliance tests are done twice a week with a blood test measuring ketone levels. To ensure that the diet is double blind in both the outpatient and inpatient phases, solid snacks are always ketogenic and shakes are either KD or SA.

Study Arms

• Active Comparator: Diet Randomization - Active Comparator
  Ketogenic diet (KD) liquid diet consists of snacks and shakes 3x p/day (high in fat). SA will receive the same KD solid snacks, in order to keep the diets blind to participants. KD will be eucaloric such that a standard equation based on weight, height, sex and age will be used to determine how many calories are provided to each participant.
  Intervention: Other: 1. Ketogenic Diet (KD) / Standard American (SA) Meals and Shakes
• Placebo Comparator: Diet Randomization - Placebo Comparator
  Standard American (SA) diet consists of KD snacks and shakes 3x p/day (high in fat) in the proportions of carbohydrates, protein and fat of traditional western diet. SA will receive the same KD solid snacks, in order to keep the diets blind to participants. SA will be eucaloric such that a standard equation based on weight, height, sex and age will be used to determine how many calories are provided to each participant.
  Intervention: Other: 1. Ketogenic Diet (KD) / Standard American (SA) Meals and Shakes

Publications *

• Zhang R, Tomasi D, Shokri-Kojori E, Manza P, Feldman DE, Kroll DS, Biesecker CL, McPherson KL, Schwandt M, Wang GJ, Wiers CE, Volkow ND. Effect of detoxification on N3 sleep correlates with brain functional but not structural changes in alcohol use disorder. Drug Alcohol Depend. 2022 Sep 1;238:109545. doi: 10.1016/j.drugalcdep.2022.109545. Epub 2022 Jun 26.
• Bornebusch AB, Mason GF, Tonetto S, Damsgaard J, Gjedde A, Fink-Jensen A, Thomsen M. Effects of ketogenic diet and ketone monoester supplement on acute alcohol withdrawal symptoms in male mice. Psychopharmacology (Berl). 2021 Mar;238(3):833-844. doi: 10.1007/s00213-020-05735-1. Epub 2021 Jan 7.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 18, 2017): 100
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2025
• Estimated Primary Completion Date: December 31, 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

• INCLUSION CRITERIA:

Patients with AUD

1. Age 18 years and older.
2. Ability to provide written informed consent as determined by clinical examination and verbal communication. Capacity to consent will be determined by those giving the informed consent.
3. DSM-IV diagnosis of alcohol dependence or alcohol abuse or DSM 5 diagnosis of moderate or severe AUD (established through history and clinical exam).
4. Participants seeking treatment for their AUD (self-report)
5. Minimum 5-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 [self-report]).
6. Alcohol specified as the preferred drug (self-report).
7. NIH employees with an AUD may participate in this study.

EXCLUSION CRITERIA:

1. Unwilling or unable to refrain from use, within 24 hours of MRI and NPT procedures, psychoactive medications or medication that may affect study results (e.g., analgesics containing narcotics, antibiotics [must finish course at least 24 hours prior to a scheduled procedure], antidiarrheal preparations, anti-inflammatory drugs [systemic corticosteroids are exclusionary], antinauseants, cough/cold preparations) (self-report, medical history). The following medications are allowable for entry on this study: analgesics (non-narcotic); antacids; antiasthma agents that are not systemic corticosteroids; antifungal agents for topical use; antihistamines (non-sedating); H2-Blockers/PPI (proton pump inhibitors); laxatives. The use of antihyperlipidemics and/or diuretics are permitted as long as they have been taken for at least 1 month before procedure visits and dose has been stabilized.
2. Current DSM-IV or DSM 5 diagnosis of a major psychiatric disorder (other than alcohol and nicotine use disorders, or substance use disorders that are mild/moderate) that required hospitalization, or that required daily medications for over 4 weeks in the past year (i.e., antidepressants; anticholinergics; antipsychotics; anxiolytics; lithium; psychotropic drugs not otherwise specified (nos) including herbal products (no drugs with psychomotor effects or with anxiolytics, stimulant, antipsychotic, or sedative properties); sedatives/hypnotics). Chronic benzodiazepine use prior to alcohol detox will also be excluded. Note that nicotine and/or caffeine use will not exclude participation.

3. Chronic use of the following medications: analgesics containing narcotics; anorexics (sibuteramine); antianginal agents; antiarrhythmics; antiasthma agents that are systemic corticosteroids; antibiotics; anticoagulants; anticonvulsants; antidiarrheal preparations; antifungal agents (systemic); antihistamines (sedating); antihypertensives (except angiotensin - converting

   enzyme (ACE) inhibitors such as Lisinopril, or Angiotensin receptor blockers (ARB) such as Losartan); anti-inflammatory drugs (systemic); antineoplastics; antiobesity; antivirals (except for treatment of HSV with agents without CNS activity, e.g. acyclovir, ganciclovir, famciclovir, valacyclovir); cough/cold preparations (dextromethorphan preparations, pseudoephedrine); hormones (exceptions: thyroid hormone replacement, oral contraceptives, and estrogen replacement therapy); insulin; and muscle relaxants.

4. Major medical problems that can impact brain function or the use of a ketogenic diet (e.g., epilepsy, diabetes, liver disease, kidney disease, kidney stones (current and/or in the past), chronic metabolic acidosis or a cardiomyopathy) as determined by EKG, history and clinical exam.
5. Clinically significant laboratory findings that could affect brain function (e.g. HIV+).
6. Head trauma with loss of consciousness for more than 30 minutes (self-report, medical history).
7. Pregnant or breast-feeding: Females of childbearing potential, or with tubal ligation, or are post-menopausal and are age 60 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.
8. 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 (self-report checklist).
9. Cannot lie comfortably flat on his/her back for up to 2 hours in the MRI scanner (self-report).
10. Body weight > 550 lbs. The MR scanner bed is tested to a weight limit of 0 lbs.
11. Milk or soy allergy (self-report).

Note that subjects will not be excluded on initial screening from enrollment onto this study if their breath alcohol test is positive; or if their urine test is positive for drugs. The following guideline will be followed for positive alcohol/drug screens on study procedure days:

-If an AUD subject s breath alcohol and/or urine drug screen test is/are positive on study days (i.e., within 24 hours before study procedures except for benzodiazepines during detox, including oxazepam [Serax], the procedures will be postponed and rescheduled to another day. If the urine drug screen is positive for THCCOOH, a saliva drug screen will be performed and subject may proceed with MRI/NPT procedures if saliva results for THC are negative. We will not place a limit on rescheduling study days.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Megan S Carraco; (301) 496-5055; megan.carraco@nih.gov

Contact: Gene-Jack Wang, M.D.; (301) 496-5012; gene-jack.wang@nih.gov

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03255031
• Other Study ID Numbers: 170152; 17-AA-0152
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No
• Plan Description: .Data is analyzed by subject group and not on an individual basis.

• Current Responsible Party: National Institutes of Health Clinical Center (CC) ( National Institute on Alcohol Abuse and Alcoholism (NIAAA) )
• Original Responsible Party: Same as current
• Current Study Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Gene-Jack Wang, M.D.; National Institute on Alcohol Abuse and Alcoholism (NIAAA)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: February 8, 2023