Clinical trial NCT03878225: Does a Ketogenic Dietary Supplement Reduce Alcohol Withdrawal Symptoms in Humans?
Official title: The Ketone Mono Ester Study - Does a Ketogenic Dietary Supplement Reduce Alcohol Withdrawal Symptoms in Humans
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Alcohol Use Disorder
Alcohol Withdrawal
Ketosis
Lead sponsor: Psychiatric Centre Rigshospitalet
Sponsor class: OTHER
First posted: 2019-03-18
Enrollment: 36
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double blinded, randomized, placebo controlled
Primary purpose: TREATMENT

Brief summary: A ketogenic diet (KD) is high in fat and low in carbohydrates and induces ketosis. KD is an approved non-pharmacological therapy for drug-resistant child epilepsy. Research has shown that a KD can reduce the behavioral measures of alcohol withdrawal symptomatology in rats. Ketosis is also possible to achieve without adherence to a KD, by ingestion of a ketogenic dietary supplement. In this study, we want to investigate if the attenuating effect of the KD observed in rodents, is also applicable in humans, i.e. whether a ketogenic dietary supplement, here a ketone monoester, would be effective in suppressing alcohol withdrawal symptoms in humans.

Objective:

To test the effect of a ketogenic dietary supplement on the need for benzodiazepines in managing alcohol withdrawal syndrome in humans.

Eligibility:

Adults 18-70 years who are alcohol dependent and are seeking treatment for alcohol withdrawal syndrome in an out-patient setting.

Design:

Double blinded, randomized clinical trial. The participants will be randomized to receive either the ketone ester beverage, or a placebo beverage.

The study will be conducted over three days (72 hours), with follow-up at 1 month and 1 year after completion. A sub-set of patients will undergo Magnetic Resonance Spectroscopy (MRS) following withdrawal treatment, and again after 1 month.

Detailed description: Neuroimaging studies have shown that acute alcohol administration decreases glucose metabolism in the human brain, which was initially thought to reflect decreased brain function. However, subsequent studies showed that even low doses of alcohol, with minimal behavioral effects, also decreased baseline brain glucose metabolism and further. This led to the hypothesis that the reduction in brain glucose metabolism during alcohol intoxication reflected the brain's utilization of an alternate energy substrate, e.g. the alcohol metabolite acetate. Acetate is not a ketone body, but biochemically similar to the ketone bodies, which include acetoacetate, BHB and acetone. Ketone bodies are similarly taken up by the Monocarboxylate Transporters in neurons, and other brain tissue. A pre-clinical trial has demonstrated that the implementation of a KD for 10 days significantly reduced the behavioral measures of alcohol withdrawal symptomatology in rats. In this study, we want to investigate if the attenuating effect of the KD observed in rodents, is also applicable in humans, i.e. whether a ketogenic dietary supplement, here a ketone monoester, would be effective in suppressing alcohol withdrawal symptoms in humans.

Objectives:

We will investigate the effect of a five times daily oral administration of a ketone dietary supplement beverage vs. placebo on the need for benzodiazepines in alcohol withdrawal syndrome. The KME beverage is a supplement to standardized out-patient alcohol withdrawal treatment.

Study population:

36 participants aged 18-70 with a diagnosis of alcohol use disorder according to the DSM-V, ICD-10, and a previous history of treatment-requiring alcohol withdrawal syndrome.

Design:

Clinical double-blinded, randomized, placebo-controlled, three-day clinical trial, with an MRS (Magnetic Resonance Spectroscopy) sub-study. The participants will be randomized to receive either the ketone ester beverage, or a placebo beverage 5 times daily. Participants will be asked to register benzodiazepine use in a medication-diary during the study. Participants will be asked to self-monitor blood-glucose and ketone levels by use of fingerstick measurements. During the study patients will be evaluated for withdrawal severity, and complete questionnaires on alcohol craving, sleep, anxiety and mood.

Eligibility criteria: Inclusion Criteria KME trial

1. Between 18 and 70 years of age.
2. Ability to provide written informed consent as determined by the physical examination and verbal communication. The capacity to consent will be determined by study personnel.
3. Alcohol-dependent individuals must meet alcohol dependency syndrome criteria according to ICD-10 and alcohol use disorder according to DSM-5, have a score \>15 on the Alcohol Use Disorder Identification Test (AUDIT) and a history of previous treatment for alcohol withdrawal syndrome following cessation of alcohol use.

Inclusion Criteria Healthy Volunteers for MRS sub-study

1. Between 18 and 70 years of age.
2. Ability to provide written informed consent as determined by the physical examination and verbal communication. The capacity to consent will be determined by study personnel.
3. Light drinkers (LD): Alcohol consumption less than 7 drinks per week typically over the past year and no more than three drinks per occasion. AUDIT score below 7 in the Alcohol Use Disorder Identification Test.
4. Heavy drinkers (HD): Not treatment-seeking and not fulfilling criteria for alcohol dependence syndrome according to ICD-10 or alcohol use disorder according to DSM-5. For at least one-year consuming alcohol at a typical rate of above a level of 14 drinks per week for men and consume at least 4 drinks per day at least once per week. For females, consume alcohol in excess of 11 drinks per week and exceed 3 drinks per day at least once per week.
5. Long term sober (LTS): For the long-term sober group, a previous diagnosis of alcohol dependence, consumed no alcohol in the previous 6 months.

Exclusion Criteria KME trial and MRS sub-study

1. Diagnosis of current psychiatric disorder that is deemed not stable by the study physician, except for the following:

   * Diagnosis of nicotine dependence
   * Alcohol withdrawal patients may have a diagnosis of alcohol dependence
   * HD may have a diagnosis of alcohol abuse
2. Lifetime diagnosis of bipolar disorder, schizophrenia, paranoid psychosis or mental retardation.
3. Incapable of understanding and/or speaking Danish.
4. Head trauma with loss of consciousness for more than 60 minutes (self-report, medical history).
5. Lifetime diagnosis of epilepsy.
6. Alcohol withdrawal seizures within the previous 3 months.
7. Use of any medication that could interfere with study assessments, including anticonvulsants, benzodiazepines and non-benzodiazepine hypnotics (Zopiclone and/or Zolpidem). Use of medications will be reviewed by a study physician on a case by case basis.
8. Body Mass Index, BMI, \< 18.5 kg/m2 or body weight \<60 kg or \>120kg.
9. Urine positive for cocaine, amphetamines, methadone, opioids or benzodiazepines.
10. Blood glucose \>12.2 mmol/L on finger-prick measurement (\>7.0 if over-night fasted).
11. Known kidney disease, pancreatic disease, porphyria or other mitochondrial diseases, type 1 diabetes, type 2 diabetes or any other history of severe somatic illness that the investigator believes would interfere with trial participation.
12. Known cirrhosis or clinical evidence of significant liver disease, such as ascites or hepatosplenomegaly.
13. Following a low-carbohydrate diet, intermittent fasting diet or consuming nutritional ketone supplements.
14. Other substance use dependency than alcohol and/or nicotine and/or cannabis within the previous 1 month.
15. Benzodiazepine dependence within the previous 1 month and/or use of benzodiazepines within the previous 14 days.
16. Females of childbearing potential who are pregnant, breast-feeding or have intention of becoming pregnant within the next 4 months, or are not using contraceptives (during the whole study period) considered as highly effective (combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable) intrauterine device - IUD, IUS, bilateral tubal occlusion, vasectomized partner, sexual abstinence) (HMA - Clinical Trials Facilitation and Coordination Group, 2014).
17. Participated in a clinical trial with investigational medication or weight reduction within the previous three months.
18. Use of Disulfiram (Antabus) in the previous 14 days prior to any planned KME ingestion or MRS procedure.
19. For HD and LD groups in MRS sub-study only: Inability to abstain from alcohol for 24 hours, to reduce risks and to avoid confounding results with alcohol withdrawal.
20. For HD and LD in MRS sub-study only: History of alcohol use disorder or alcohol withdrawal symptoms requiring medication
21. For participants undergoing MRS (all HD, LD, and LTS, some KME patients): Implanted metallic devices or objects that could potentially prove harmful when exposed to the MRS environment or procedures. Patients in the alcohol withdrawal group can still participate in the KME study if meeting this criterion, but cannot undergo subsequent MRS.
22. Any condition that the investigator estimates would interfere with trial participation and/or the safety of the participant.

Primary outcomes:
measure: Benzodiazepine use
timeFrame: 2 years
measure: Magnetic Resonance Spectroscopy sub-study
timeFrame: 2 years
Secondary outcomes:
measure: Sleep quality
timeFrame: 2 years
measure: Alcohol withdrawal symptoms.
timeFrame: 2 years
measure: Anxiety
timeFrame: 2 years
measure: Alcohol craving
timeFrame: 2 years
measure: Alcohol intake
timeFrame: 2 years
measure: Mood
timeFrame: Assess mood measured by VAS questionnaires during the trial, and by the Major Depressive Inventory (MDI) at screening and one-month follow-up
Other outcomes:
Locations:
city: Lyngby
country: Denmark
facility: Novavi Lyngby
state: Danmark (DK)
city: Copenhagen
country: Denmark
facility: Psychiatric Center Copenhagen, Rigshospitalet
Study officials:
affiliation: Psychiatric Center Copenhagen, Rigshospitalet
name: Anders Fink-Jensen, MD, DMSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.