Lacosamide Effects on Alcohol Self Administration and Craving in Heavy Drinkers

Study Overview
=================
Brief Summary
-----------------
This is a double-blind, randomized, placebo-controlled, crossover design trial tested the effect of lacosamide on alcohol self-administration and craving following a priming dose of alcohol. The specific objective of this study was to determine whether lacosamide, a novel anticonvulsant that is FDA-approved for treating partial seizures, has effects on alcohol craving and consumption.

Detailed Description
-----------------
The present proposal was intended to answer the call for accelerating drug development by exploring the potential of a novel anticonvulsant, lacosamide, as a candidate medication for the treatment of alcohol use disorder (AUD). This drug, which is approved for the treatment of seizure disorders, has unique pharmacological actions that include enhancement of slow sodium channel inactivation and inhibition of collapsin response mediator protein-2 (CRMP-2). Alcohol consumption in mice that had knockdown of CRMP-2 within the nucleus accumbens was decreased from levels seen in control animals. In rodent studies, lacosamide administration has produced reductions in 'excessive' drinking and has experimentally-induced decreased expression of the CRMP-2 protein. These findings implicate CRMP-2 as playing a role in the regulation of alcohol consumption. None of the FDA-approved AUD medications or medications commonly used off-label to treat AUD target this CRMP-2 pathway, making lacosamide a promising compound for AUD drug development. The aims of this study were to: 1) test the effects of lacosamide on alcohol self-administration and craving, 2) test the effects of 7 days of lacosamide administration on cognitive function, and 3) test the effects of lacosamide on alcohol consumption and craving during a 7-day period of exposure. The effects of 7 days of lacosamide (300mg) or placebo were evaluated in a human laboratory using an alcohol self-administration methodology. In this within-subjects crossover design, heavy drinkers (N=27) were randomized to the order of exposure (lacosamide or placebo) prior to completing two alcohol self-administration trials. Subjects received a priming drink of alcohol and had access to 8 alcoholic drinks over a 2-hour period. The investigators anticipated that subjects would consume less alcohol during an alcohol self-administration trial when receiving lacosamide compared to when they are receiving placebo. Significant lacosamide-induced reductions in the quantity of alcohol self-administered are considered to be an indication that this drug may have value as an AUD medication. This study may provide a rationale for phase II clinical studies testing lacosamide with a treatment-seeking AUD population. These results should also help to spur further pre-clinical investigation into the role play by CRMP-2 in regulating both alcohol consumption and alcohol seeking behaviors.

Official Title
-----------------
Lacosamide Effects on Alcohol Self Administration and Craving in Heavy Drinkers

Conditions
-----------------
Alcohol Use Disorder

Intervention / Treatment
-----------------
* Drug: Lacosamide
* Drug: Placebo oral capsule


Participation Criteria
=================
Eligibility Criteria
-----------------
Subject Inclusion Criteria 21-55 years of age Can provide proof of age with state-issued or federal picture ID Exceeds safe weekly drinking limits (≥14 drinks for women or ≥21 drinks for men per week) Reports at least an average of one episode per week of binge drinking (>3 for women, >4 for men) in the four weeks prior to baseline screening Meets DSM-5 criteria for mild alcohol use disorder or greater severity. Has a smartphone to complete some of the study assessments. Subject Exclusion Criteria Currently seeking treatment for alcohol problems Clinical Institute Withdrawal Assessment at >10 DSM-5 diagnosis of current major depression, bipolar disorder, schizophrenia, bulimia/anorexia, dementia, or a substance use disorder other than alcohol, nicotine, marijuana or caffeine If female, pregnant, nursing, or have plans to become pregnant If female, does not agree to use an accepted form of birth control Is currently using medications for which alcohol is a contraindication Has a medical or mental health condition for which further alcohol exposure at the planned dose range would be contraindicated. Current risk of suicidality (MINI suicidality score greater than 8 (low risk) or Yes to the ideation question #4 of the C-SSRS) Has a history of myocardial infarction, congestive heart failure, has a risk for the development of heart block, or are taking medications that can decrease conduction through the atrial ventricular node. Has previous exposure to lacosamide Has received any form of counseling, self-help, pharmacotherapy, or other intervention to treat AUD in the past 90 days. Is unwilling to suspend use of multivitamins that contain riboflavin during study participation Has urine toxicology results positive for cocaine, opioids, amphetamines, buprenorphine, methadone, or methamphetamines Liver function values AST or ALT are twice the normal limit GFR <80 mL/min Unable to comfortably abstain from nicotine for a period of 8 hours.

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a double-blind, randomized, placebo-controlled, crossover design trial to test the effect of lacosamide on alcohol self-administration and craving following a priming dose of alcohol.This study is a within subjects design in which each subject receives both study drug (lacosamide) and placebo during participation.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lacosamide<br>Lacosamide titration was done to a target dose of 300mg. Participants took 100 mg of lacosamide once on day 1, 100 mg twice per day from day 2 through day 6 (200 mg daily total), on day 7 the lacosamide dose was increased to 150 mg twice daily (300 mg daily total), and on day 8 the participant took one dose of 150 mg. | Drug: Lacosamide<br>* Lacosamide titration was done to a target dose of 300mg. Participants took 100 mg of lacosamide once on day 1, 100 mg twice per day from day 2 through day 6 (200 mg daily total), on day 7 the lacosamide dose was increased to 150 mg twice daily (300 mg daily total), and on day 8 the participant took one dose of 150 mg.<br>* Other names: Vimpat;|
| Placebo Comparator: Placebo oral capsule<br>Participants took a placebo oral capsule once on day 1, twice per day from day 2 to day 7, and once on day 8. | Drug: Placebo oral capsule<br>* Participants took a placebo oral capsule once on day 1, twice per day from day 2 to day 7, and once on day 8.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alcohol Consumption in Alcohol Self-Administration Trials | Alcohol consumption will be measured by using a graduated cylinder to determine the amount of alcohol given to the subject that was consumed. This outcome will be measured as standard drink units. A standard drink contains approximately 0.6 fluid ounces of pure alcohol. | 2 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Verbal Fluency: Controlled Word Association (COWAT) | The Controlled Word Association (COWAT) is a verbal fluency test that measures the spontaneous production of words beginning with some designated letter. The participant is asked to name words beginning with a given letter, excluding proper nouns, for one minute and this procedure is repeated three times with a different letter each time. A different set of letters was used in each of the two alcohol self-administration trials: C-F-L and P-R-W. The examiner writes down the words provided by the participant on a piece of paper. This test is scored by counting the number of words generated by the subject for each letter, then adding the scores for each of the three letters to calculate a total test score. The lowest possible score is 0 and there is no upper limit to the score range. A higher score is indicative of better outcomes (I.e. better verbal fluency). | 3 minutes | 
| Cognitive Function: Spatial Span Forward | The Wechsler Memory Scale (WMS-III) Spatial Span test will be used to assess subjects' working memory. Subjects will be shown a sequence of block tapping and asked to repeat back an increasing number of tapped blocks in the same order. Each of the 16 items on this test is scored 0 (incorrect answer) or 1 (correct answer). The total score is calculated by adding the scores for each of the 16 items. The total score range is 0-16. Higher scores are indicative of higher levels of working memory (better outcome) and lower scores are indicative of lesser working memory function (worse outcome). | 10 minutes | 
| Cognitive Function: Spatial Span Backward | The Wechsler Memory Scale (WMS-III) Spatial Span test will be used to assess subjects' working memory. Subjects will be shown a sequence of block tapping and asked to repeat back an increasing number of tapped blocks in the opposite order. Each of the 16 items on this test is scored 0 (incorrect answer) or 1 (correct answer). The total score is calculated by adding the scores for each of the 16 items. The total score range is 0-16. Higher scores are indicative of higher levels of working memory (better outcome) and lower scores are indicative of lesser working memory function (worse outcome). | 10 minutes | 
| Cognitive Function: Digit Span Forward | The Wechsler Adult Intelligence Scale (WAIS-IV) Digit Span test will be used to assess subjects' working memory. Subjects will be read and asked to repeat back an increasing number of digits in the same order. Each of the 16 items on this test is scored 0 (incorrect answer) or 1 (correct answer). The total score is calculated by adding the scores for each of the 16 items. The total score range is 0-16. Higher scores are indicative of higher levels of working memory (better outcome) and lower scores are indicative of lesser working memory function (worse outcome). | 10 minutes | 
| Cognitive Function: Digit Span Backward | The Wechsler Adult Intelligence Scale (WAIS-IV) Digit Span test will be used to assess subjects' working memory. Subjects will be read and asked to repeat back an increasing number of digits in the opposite order. Each of the 16 items on this test is scored 0 (incorrect answer) or 1 (correct answer). The total score is calculated by adding the scores for each of the 16 items. The total score range is 0-16. Higher scores are indicative of higher levels of working memory (better outcome) and lower scores are indicative of lesser working memory function (worse outcome). | 10 minutes | 
| Cognitive Function: Digit Span Sequencing | The Wechsler Adult Intelligence Scale (WAIS-IV) Digit Span test will be used to assess subjects' working memory. Subjects will be read and asked to repeat back an increasing number of digits in ascending order. Each of the 16 items on this test is scored 0 (incorrect answer) or 1 (correct answer). The total score is calculated by adding the scores for each of the 16 items. The total score range is 0-16. Higher scores are indicative of higher levels of working memory (better outcome) and lower scores are indicative of lesser working memory function (worse outcome). | 10 minutes | 
| Alcohol Craving: Obsessive-Compulsive Drinking Scale (OCDS) Pretrial | The Obsessive-Compulsive Drinking Scale (OCDS) is a quick and reliable 14-item self-rating instrument that provides a total score that measures some cognitive aspects of alcohol craving (obsessive and compulsive drinking). Each of the 14 items is scored from 0 to 4. The total score is calculated by adding the scores for each of the 14 items. The total score range is 0-56. Higher scores are indicative of more obsessive or compulsive drinking and lower scores are indicative of less obsessive or compulsive drinking. | 5 minutes | 
| Alcohol Craving: Visual Analog Scale (VAS) Pretrial | Alcohol craving was measured by self report with the Visual Analog Scale (VAS). The VAS is a straight horizontal line with one end indicating no alcohol craving and the other end indicating intense alcohol craving. The participant marks a point on the line that matches their present amount of alcohol craving. Location of the point on the line is measured for a score range of 0-100. A lower score indicates less craving for alcohol and a higher score indicated more craving for alcohol. | 1 minute | 
| Alcohol Craving: Visual Analog Scale (VAS) Observation Period, Minute 10 | Alcohol craving was measured by self report with the Visual Analog Scale (VAS). The VAS is a straight horizontal line with one end indicating no alcohol craving and the other end indicating intense alcohol craving. The participant marks a point on the line that matches their present amount of alcohol craving. Location of the point on the line is measured for a score range of 0-100. A lower score indicates less craving for alcohol and a higher score indicated more craving for alcohol. | 1 minute | 
| Alcohol Craving: Visual Analog Scale (VAS) Observation Period, Minute 20 | Alcohol craving was measured by self report with the Visual Analog Scale (VAS). The VAS is a straight horizontal line with one end indicating no alcohol craving and the other end indicating intense alcohol craving. The participant marks a point on the line that matches their present amount of alcohol craving. Location of the point on the line is measured for a score range of 0-100. A lower score indicates less craving for alcohol and a higher score indicated more craving for alcohol. | 1 minute | 
| Alcohol Craving: Visual Analog Scale (VAS) Observation Period, Minute 30 | Alcohol craving was measured by self report with the Visual Analog Scale (VAS). The VAS is a straight horizontal line with one end indicating no alcohol craving and the other end indicating intense alcohol craving. The participant marks a point on the line that matches their present amount of alcohol craving. Location of the point on the line is measured for a score range of 0-100. A lower score indicates less craving for alcohol and a higher score indicated more craving for alcohol. | 1 minute | 
| Alcohol Craving: Visual Analog Scale (VAS) Observation Period, Minute 40 | Alcohol craving was measured by self report with the Visual Analog Scale (VAS). The VAS is a straight horizontal line with one end indicating no alcohol craving and the other end indicating intense alcohol craving. The participant marks a point on the line that matches their present amount of alcohol craving. Location of the point on the line is measured for a score range of 0-100. A lower score indicates less craving for alcohol and a higher score indicated more craving for alcohol. | 1 minute | 
| Alcohol Craving: Visual Analog Scale (VAS) Self-Administration Blocks 1 and 2, Minute 30 | Alcohol craving was measured by self report with the Visual Analog Scale (VAS). The VAS is a straight horizontal line with one end indicating no alcohol craving and the other end indicating intense alcohol craving. The participant marks a point on the line that matches their present amount of alcohol craving. Location of the point on the line is measured for a score range of 0-100. A lower score indicates less craving for alcohol and a higher score indicated more craving for alcohol. | 1 minute | 
| Alcohol Craving: Visual Analog Scale (VAS) Self-Administration Blocks 1 and 2, Minute 60 | Alcohol craving was measured by self report with the Visual Analog Scale (VAS). The VAS is a straight horizontal line with one end indicating no alcohol craving and the other end indicating intense alcohol craving. The participant marks a point on the line that matches their present amount of alcohol craving. Location of the point on the line is measured for a score range of 0-100. A lower score indicates less craving for alcohol and a higher score indicated more craving for alcohol. | 1 minute | 
| Alcohol Craving: Visual Analog Scale (VAS) Self-Administration Blocks 1 and 2, Minute 90 | Alcohol craving was measured by self report with the Visual Analog Scale (VAS). The VAS is a straight horizontal line with one end indicating no alcohol craving and the other end indicating intense alcohol craving. The participant marks a point on the line that matches their present amount of alcohol craving. Location of the point on the line is measured for a score range of 0-100. A lower score indicates less craving for alcohol and a higher score indicated more craving for alcohol. | 1 minute | 
| Alcohol Craving: Visual Analog Scale (VAS) Self-Administration Blocks 1 and 2, Minute 120 | Alcohol craving was measured by self report with the Visual Analog Scale (VAS). The VAS is a straight horizontal line with one end indicating no alcohol craving and the other end indicating intense alcohol craving. The participant marks a point on the line that matches their present amount of alcohol craving. Location of the point on the line is measured for a score range of 0-100. A lower score indicates less craving for alcohol and a higher score indicated more craving for alcohol. | 1 minute | 
| Alcohol Craving: Alcohol Urge Questionnaire (AUQ) Self-Administration Blocks 1 and 2, Minute 30 | The Alcohol Urge Questionnaire (AUQ) is an 8-item self report that measures the participant's urge for an alcoholic drink at the time the questionnaire is completed. Questions are in the form of a 7-point Likert scale (from strongly disagree to strongly agree) and the participant selects the extent to which they disagree or agree with the 8 statements relating to desire to drink, expectation of a desired outcome from drinking, and inability to avoid drinking if alcohol was available. Each of the 8 items is scored 1-7. The total score is calculated by adding the scores for each of the items. The total score range is 8-56. Lower scores indicate less urge for alcohol and higher scores indicate more urge for alcohol. | 1 minute | 
| Alcohol Craving: Alcohol Urge Questionnaire (AUQ) Self-Administration Blocks 1 and 2, Minute 60 | The Alcohol Urge Questionnaire (AUQ) is an 8-item self report that measures the participant's urge for an alcoholic drink at the time the questionnaire is completed. Questions are in the form of a 7-point Likert scale (from strongly disagree to strongly agree) and the participant selects the extent to which they disagree or agree with the 8 statements relating to desire to drink, expectation of a desired outcome from drinking, and inability to avoid drinking if alcohol was available. Each of the 8 items is scored 1-7. The total score is calculated by adding the scores for each of the items. The total score range is 8-56. Lower scores indicate less urge for alcohol and higher scores indicate more urge for alcohol. | 1 minute | 
| Alcohol Craving: Alcohol Urge Questionnaire (AUQ) Self-Administration Blocks 1 and 2, Minute 90 | The Alcohol Urge Questionnaire (AUQ) is an 8-item self report that measures the participant's urge for an alcoholic drink at the time the questionnaire is completed. Questions are in the form of a 7-point Likert scale (from strongly disagree to strongly agree) and the participant selects the extent to which they disagree or agree with the 8 statements relating to desire to drink, expectation of a desired outcome from drinking, and inability to avoid drinking if alcohol was available. Each of the 8 items is scored 1-7. The total score is calculated by adding the scores for each of the items. The total score range is 8-56. Lower scores indicate less urge for alcohol and higher scores indicate more urge for alcohol. | 1 minute | 
| Alcohol Craving: Alcohol Urge Questionnaire (AUQ) Self-Administration Blocks 1 and 2, Minute 120 | The Alcohol Urge Questionnaire (AUQ) is an 8-item self report that measures the participant's urge for an alcoholic drink at the time the questionnaire is completed. Questions are in the form of a 7-point Likert scale (from strongly disagree to strongly agree) and the participant selects the extent to which they disagree or agree with the 8 statements relating to desire to drink, expectation of a desired outcome from drinking, and inability to avoid drinking if alcohol was available. Each of the 8 items is scored 1-7. The total score is calculated by adding the scores for each of the items. The total score range is 8-56. Lower scores indicate less urge for alcohol and higher scores indicate more urge for alcohol. | 1 minute | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Lacosamide, Alcohol craving, Alcohol Urge Questionnaire, Obsessive-Compulsive Drinking Scale, Visual Analog Scale, Alcohol consumption, Alcohol use disorder