A proof-of-concept investigation into ketamine as a pharmacological treatment for alcohol dependence: study protocol for a randomised controlled trial

Abstract

Background: Worldwide, alcohol abuse is a burgeoning problem. Abstinence is key to allow recovery of physical and mental health as well as quality of life, but treatment for alcohol dependence is associated with high relapse rates. Preliminary data have suggested that a combined repeated ketamine and psychological therapy programme may be effective in reducing relapse in severe alcohol use disorder. This non-commercial proof-of-concept trial is aimed at making a preliminary assessment of the effectiveness of this combined treatment in this patient group.

Methods/design: This is a phase II, randomised, double-blind, placebo-controlled, parallel-group clinical trial taking place in two sites in the UK: the South West of England and London. Ninety-six recently detoxified alcoholics, with comorbid depressive symptoms, will be randomised to one of four treatment arms. Patients will receive either three sessions of ketamine (0.8 mg/kg administered intravenously (IV) over 40 minutes) or placebo (50 ml saline 0.9% IV over 40 minutes) plus either seven sessions of manualised psychological therapy or an alcohol education control. Patients will be assessed at 3 and 6 months on a range of psychological and biological variables. The primary endpoints are (1) relapse rates at 6 months and (2) percentage days abstinent at 6 months. Secondary endpoints include 3 and 6 month percentage days abstinence, tolerability (indicated by dropout), adverse events, depressive symptoms, craving and quality of life.

Discussion: This study will provide important information on a new combined psychological and pharmacological intervention aimed at reducing relapse rates in alcoholics. The findings would have broad application given the worldwide prevalence of alcoholism and its associated medical, psychological and social problems.

Trial registration: ClinicalTrials.gov, NCT02649231 . Registered on 5 January 2016.

Keywords: Alcoholism; Depression; Ketamine; Relapse.

Fig. 1

KARE trial design. Step 1: Participants are initially identified and go through pre-screening. Step 2: If eligible, participants are invited for a screening visit to further determine eligibility. Step 3: If eligible, participants are randomised into one of four treatment conditions: (1) ketamine + relapse prevention therapy, (2) ketamine + alcohol education, (3) placebo + relapse prevention therapy, (4) placebo + alcohol education. Treatment runs over 7 sessions (1 therapy/education per session, ketamine/placebo is administered in 3 sessions). Step 4: Participants are followed up at 12 weeks. Step 5: Participants are followed up at 24 weeks

Fig. 2

KARE trial SPIRIT checklist. This checklist contains all trial-specific assessments that will be run on each study visit. An ‘X’ denotes that this assessment will be run. * Physical examination: cardiovascular, respiratory, gastrointestinal and neurological assessment to a level of detail that would be expected for a patient due to receive anesthesia. ** Vital Signs: Resting pulse, pulse oximetry and blood pressure for safety monitoring. Vital signs will also be continuously monitored throughout the infusion until the participant has recovered. X^a Bloods: Full Blood Count (haemoglobin, white cell count, platelets, mean red cell volume); Liver Function Tests (Bilirubin, Alanine aminotransferase, Asparate aminotransferase, Total Protein, Alkaline phosphatase, Albumin, Globulin, gamma-glutamyl transpeptidase), Biochemistry (urea, sodium, potassium, glucose, calcium, thyroid stimulating hormone). X^b Bloods: Liver Function Tests (same as above); Brain-derived neurotrophic factor; ketamine. X^c Urine drug screen panel (methamphetamine, cocaine, tetrahydrocannabinol, benzodiazepines, tricyclic antidepressants, barbiturates, phencyclidine, amphetamines, morphine, methadone) including ketamine. X^d Urine drug screen panel (same as above) excluding ketamine