Primary Alcohol Use Disorder
Conditions
Brief summary
96 recently detoxified alcoholics will be randomized to receive either 3 sessions ketamine (0.8 mg/kg IV over 45 minutes) or placebo plus manualised psychological therapy, or 3 sessions of ketamine or placebo plus simple psychoeducation. Patients will be assessed at 3 and 6 months on a range of psychological and biological variables. Primary endpoints will be % days abstinent at 6 months and relapse rates at 6 months. Secondary endpoints include depressive symptoms, craving, quality of life.
Interventions
DRUGKetamine
0.8 mg/kg ketamine
DRUGPlacebo
0.9% saline
BEHAVIORALPsychological Therapy
Manualised relapse prevention based CBT
BEHAVIORALAlcohol Education
Simple education about alcohol effects
Sponsors
University College, London
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Meet either a) DSM-5 criteria for severe alcohol use disorder and b) DSM-IV criteria for alcohol dependence within the last 12 months; * Currently abstinent from alcohol (breathalyser BAC level 0.00) and negative urine drug screening (participants testing positive for THC who do not have a history or current cannabis dependency may be included); * Minimum of mild depression(\>14 on Beck Depression Inventory-II); * Capacity to give informed consent as defined by GCP guidelines; * Willing and able to wear SCRAM-X bracelet for 6 months; * Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal or barrier method of birth control; True abstinence) from the time consent is signed until 6 weeks after treatment discontinuation and inform the trial if pregnancy occurs. For the purpose of clarity, True abstinence is when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence, withdrawal, spermicides only or lactational amenorrhoea method for the duration of a trial, are not acceptable methods of contraception; * Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for trial treatment and on day of first treatment.
Exclusion criteria
* Currently taking any other relapse prevention medication or anti-depressants; * Uncontrolled hypertension, systolic 140mm Hg or greater and diastolic 90mm Hg or greater; * \<16 or \> 35 BMI * History of psychosis, or in a first-degree relative as identified by DSM-5 or DSM-IV SCID; co-morbid current psychiatric diagnosis excluding depression, identified via self-reported or identified by a medical professional; * Previous or current diagnosis of substance dependence / severe substance misuse disorder; * History of neuropsychological difficulties * One or more previous confirmed seizures; * Currently taking daily prescribed medication contraindicated in the SPC with ketamine: 1. Barbiturates and/or narcotics 2. Atracurium and tubocurarine 3. Central nervous system (CNS) depressants (e.g. phenothiazines, sedating H1 - blockers or skeletal muscle relaxants) 4. Anxiolytics, sedatives and hypnotics 5. Thiopental, thyroid hormones 6. Antihypertensive agents 7. Theophylline and methylxanthines. 8. Halogenated anaesthetics 9. OR psychotropic drug use at screening assessments or during treatment weeks * Liver function tests \> 3 times normal levels * Where there are special warnings or precautions for use according to the SPC and where risk vs benefit ratio is not in favour of giving ketamine, with assessment made by physical examination by medically qualified trial personnel, self-report or inspection of the medical notes: 1. Acute intermittent porphyria 2. Dehydration or hypovolemia 3. Hyperthyroidism, or patients receiving thyroid replacement 4. Pulmonary or upper respiratory tract infection 5. Severe Coronary artery disease, Cerebrovascular accident or cerebral trauma 6. Diabetes 7. Known glaucoma or globe injuries 8. Cirrhosis 9. Epilepsy 10. Neurological condition/brain damage 11. Intracranial mass lesions, presence of head injury or hydrocephalus * Suicidal ideation. * Not willing to use effective contraception or (females) take pregnancy test; * Allergic reaction to ketamine; * \>10 previous detoxifications from alcohol; * Pregnant or breastfeeding; * Allergies to excipients of IMP or placebo; * Use of another experimental investigational medicinal product that is likely to interfere with the study medication within 3 months of study enrolment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Relapse Rates | 6 months | Time line follow back |
| Percentage Days Abstinent | 6 months | Time line follow back |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ketamine+Psychological Therapy Ketamine with psychological therapy
Ketamine: 0.8 mg/kg ketamine
Psychological Therapy: Manualised relapse prevention based CBT | 24 |
| Ketamine+Education ketamine with alcohol education
Ketamine: 0.8 mg/kg ketamine
Alcohol Education: Simple education about alcohol effects | 24 |
| Placebo+Psychological Therapy placebo with psychological therapy
Placebo: 0.9% saline
Psychological Therapy: Manualised relapse prevention based CBT | 23 |
| Placebo+Education placebo with alcohol education
Placebo: 0.9% saline
Alcohol Education: Simple education about alcohol effects | 25 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 1 | 1 | 0 |
| Overall Study | Protocol Violation | 2 | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Ketamine+Education | Placebo+Psychological Therapy | Placebo+Education | Total | Ketamine+Psychological Therapy |
|---|---|---|---|---|---|
| Age, Continuous | 40.5 years STANDARD_DEVIATION 11.1 | 47.0 years STANDARD_DEVIATION 11.8 | 43.7 years STANDARD_DEVIATION 10.2 | 44.1 years STANDARD_DEVIATION 10.6 | 45.2 years STANDARD_DEVIATION 8.7 |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants | — |
| Region of Enrollment United Kingdom | 24 participants | 23 participants | 25 participants | 96 participants | 24 participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 10 Participants | 35 Participants | 10 Participants |
| Sex: Female, Male Male | 17 Participants | 15 Participants | 15 Participants | 61 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 | 0 / 23 | 0 / 25 |
| other Total, other adverse events | 13 / 24 | 17 / 24 | 16 / 23 | 17 / 25 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 | 2 / 23 | 1 / 25 |
Outcome results
Primary
Percentage Days Abstinent
Time line follow back
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketamine+Psychological Therapy | Percentage Days Abstinent | 86.4 percentage of days abstinent | Standard Deviation 17.7 |
| Ketamine+Education | Percentage Days Abstinent | 82.5 percentage of days abstinent | Standard Deviation 20 |
| Placebo+Psychological Therapy | Percentage Days Abstinent | 78.3 percentage of days abstinent | Standard Deviation 26.9 |
| Placebo+Education | Percentage Days Abstinent | 70.7 percentage of days abstinent | Standard Deviation 25.1 |
Comparison: Linear regression modelling was used to compare the ketamine group with the placebo group (combined across therapy and psychoeducation). Only participants with a minimum of 159 days of completed drinking self-report data were included in the main ITT analysis as this was the shortest duration of time before any participant completed the 6 month (23-25 week) follow up in the study. Reporting time was capped at 180 days.95% CI: [1.1, 19]
Primary
Relapse Rates
Time line follow back
Time frame: 6 months
Population: To explain discrepancies between overall number of participants analysed and the flow diagram: Only participants with a minimum of 159 days of completed drinking self-report data were included in the main analysis of alcohol relapse status as this was the shortest duration of time before any participant completed the 6 month (23-25 week) follow up in the study. Reporting time was capped at 180 days.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ketamine+Psychological Therapy | Relapse Rates | 13 Participants |
| Ketamine+Education | Relapse Rates | 15 Participants |
| Placebo+Psychological Therapy | Relapse Rates | 14 Participants |
| Placebo+Education | Relapse Rates | 18 Participants |
Comparison: Confirmed alcohol relapse by drug condition at 6 months using the Alcohol Timeline-Followback. Logistic regression modelling was used to compare the ketamine group with the placebo group (combined across therapy and alcohol education).95% CI: [0.28, 1.75]