Conditions: Alcohol Use Disorder
Keywords: Lacosamide Alcohol craving Alcohol Urge Questionnaire Obsessive-Compulsive Drinking Scale Visual Analog Scale Alcohol consumption Alcohol use disorder
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 66
Healthy volunteers: no

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.

Arms:
arm 1: 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. arm 2: Participants took a placebo oral capsule once on day 1, twice per day from day 2 to day 7, and once on day 8.

Interventions: intervention 1: Lacosamide intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: 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. intervention 2: Participants took a placebo oral capsule once on day 1, twice per day from day 2 to day 7, and once on day 8.

Protocol document:
Prot_SAP_000.pdf: 
Lacosamide effects on alcohol self administration and craving in heavy drinkers   
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LACOSAMIDE EFFECTS ON ALCOHOL SELF ADMINISTRATION AND  
CRAVING IN HEAVY DRINKERS 
 
ClinicalTrials.gov number: NCT03271528 
Protocol Version Number: 3.12 
Protocol Version Date: 3.11.19 
Sponsor:  NIAAA/NIH 
Principal Investigator:  Eric G. Devine, Ph.D. 
 
Phone: 617-638-7888 
 
E-mail: eric.devine@bmc.org 
 
CONFIDENTIAL 
 
This document is confidential and the property of Boston Medical Center.   No part of it 
may be transmitted, reproduced, published, or used by other persons without prior written 
authorization from the study sponsor. 


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TABLE OF CONTENTS 
1 List of Abbreviations ................................................................................................................ 3 
2 Protocol Summary .................................................................................................................... 3 
3 Background/Rationale & Purpose............................................................................................. 4 
3.1 
Background Information ................................................................................................. 4 
3.2 
Rationale and Purpose ..................................................................................................... 7 
4 Objectives ................................................................................................................................. 7 
4.1 
Study Objectives ............................................................................................................. 7 
4.2 
Study Outcome Measures ................................................................................................ 7 
4.2.1 
Primary Outcome Measures .............................................................................. 7 
4.2.2 
Secondary Outcome Measures .......................................................................... 7 
5 Study Design ............................................................................................................................. 8 
6 Potential Risks and Benefits ..................................................................................................... 8 
6.1 
Risks ................................................................................................................................ 8 
6.2 
Potential Benefits .......................................................................................................... 13 
6.3 
Analysis of Risks in Relation to Benefits ...................................................................... 13 
7 Study Subject Selection .......................................................................................................... 14 
7.1 
Subject Inclusion Criteria .............................................................................................. 14 
7.2 
Subject Exclusion Criteria ............................................................................................. 14 
8 Study Intervention ................................................................................................................... 15 
9 Study Procedures .................................................................................................................... 16 
10 Assessment of Safety and Data Safety Monitoring Plan (DSMP) .......................................... 19 
10.1 Definitions ..................................................................................................................... 19 
10.2 Safety Review ............................................................................................................... 20 
10.3 Reporting Plans ............................................................................................................. 22 
10.4 Stopping Rules .............................................................................................................. 22 
11 Data Handling and Record Keeping ....................................................................................... 23 
11.1 Confidentiality ............................................................................................................... 23 
11.2 Source Documents ......................................................................................................... 23 
11.3 Case Report Forms ........................................................................................................ 23 
11.4 Study Records Retention ............................................................................................... 24 
12 Statistical Plan ......................................................................................................................... 25 
12.1 Study Hypotheses and Proposed Analyses .................................................................... 25 
12.2 Sample Size Determination ........................................................................................... 25 
13 Ethics/Protection of Human Subjects ..................................................................................... 26 
14 Literature References .............................................................................................................. 26 
15.  Appendix A: Schedule of Events ........................................................................................... 32 


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1 
List of Abbreviations 
 
Abbreviation 
Abbreviation definition 
Alcohol Use Disorder 
AUD 
 
2 
Protocol Summary 
Title: 
Lacosamide effects on alcohol self administration and craving 
in heavy drinkers. 
Population: 
The present study will involve 112 men and women aged 21 to 
55 who exceed safe levels of drinking.  Women and minorities 
who meet the study criteria will be eligible to participate. No 
vulnerable populations are being targeted for inclusion in this 
study 
Intervention: 
Eligible subjects will be titrated to a target dose of 300mg of 
lacosamide (or a matched placebo) over a 7-day period.  A 
riboflavin tracer will be added to each capsule to serve as an 
objective measure of medication adherence.  Subjects will 
receive a single 150 mg dose of lacosamide on day 8.  Subjects 
will take study medication by mouth.  Subjects will receive 
alcohol in the laboratory on day 8 in an alcohol craving 
challenge.  Subjects will be presented with four drinks, each 
mixed to raise their BAL 0.015g/dl. They will be told that they 
can either consume the desired number of drinks over the 
following 60 minutes or they will receive the equivalent in a 
cash reward.  This procedure will be repeated with an 
additional 4 drinks after 60 minutes has elapsed.  Subjects will 
serve as their own controls.  The intervention will be repeated 
with a placebo/lacosamide after a washout period. The order of 
lacosamide and placebo dosing will be randomized.     
Objectives: 
The specific objective of this study is to determine whether 
lacosamide, a novel anticonvulsant that is FDA-approved for 
treating partial seizures, has effects on alcohol craving and 
consumption.  This medication is a promising candidate that 
has unique actions on voltage-gated sodium channels and may 
have inhibitory effects on collapsin response mediator protein-
2 (CRMP-2).  Testing the effects of lacosamide on drinking is 
a compelling opportunity that is consistent with the mission of 
NIAAA to evaluate the efficacy of re-purposed compounds 
with novel mechanisms that have the potential to treat AUD.  
If successful, this study could lead to a phase II randomized 
controlled trial to test lacosamide as a treatment for AUD.  The 
specific goal of this study is to evaluate the effects of 
lacosamide on drinking and craving among heavy drinkers in a 
human laboratory using an alcohol self-administration 


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paradigm.   
 
 
Design/Methodology: This is a double-blind, randomized, placebo-controlled, 
crossover design trial that will test the effect of lacosamide on 
alcohol self-administration and craving following a priming 
dose of alcohol.  An established human laboratory self-
administration procedure will be followed.  Each subject will 
complete 5 clinic visits over a period of up to 44 days of 
participation.  Study participation is comprised of a baseline 
assessment, randomization visit, alcohol self administration 
Trial 1, an assessment visit to verify continued eligibility and 
dispense medication, and a second alcohol self-administration 
Trial.  The volume of alcohol consumed during alcohol 
challenge trials 1 and 2 will be used to test the effect of 
lacosamide on alcohol consumption.  Craving measures (AUQ 
and VAS) collected during the self-administration trials will be 
used to test the effect of lacosamide on alcohol craving.   
Total Study 
Duration: 
The entire study will take 24 months to complete. 
Subject Participation 
Duration: 
Each subject’s length of participation will be up to 44 days.   
 
3 
Background/Rationale & Purpose 
 
3.1 
Background Information 
Current models of care for treating Alcohol Use Disorder (AUD) include both behavioral 
therapies and pharmacotherapy1.  Although pharmacotherapy for AUD in the US has been 
available since 1948 when disulfiram was approved, options for treatment are limited as there are 
only four medications which have been approved by the FDA for treating AUD.  Disulfiram, 
naltrexone, acamprosate, and long-acting naltrexone have all shown promise as agents to treat 
AUD2 but no single medication has proven to be effective across the heterogeneous groups of 
people with AUD3. Movement towards models of personalized care and pharmacogenetic 
treatment matching4-5 hold some promise for improving AUD treatment outcomes, but the 
limited number of unique mechanisms of action of the currently approved drugs presents a 
challenge to implementing this model of care.  Unfortunately, few novel compounds to treat 
AUD progress to phase II trials, and developing novel compounds is both costly and time-
consuming6.  One pathway of drug development efforts has been focused on re-purposing FDA 
approved medications that have promising mechanistic effects7 and some success has been 
achieved in using this strategy with anticonvulsants8.  Identification of additional drugs with 
unique mechanisms of action that are found to reduce alcohol consumption could expand the 
treatment options and further the goal of personalized care for AUD.  The overarching goal of 
our research is to identify agents with unique mechanisms that hold promise for treating AUD.  
The specific objective of this study is to determine whether lacosamide, a novel anticonvulsant 
that is FDA-approved for treating partial seizures, has effects on alcohol craving and 


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consumption.     
Alcohol Use Disorder as a national health problem 
More than 16 million adults suffer from Alcohol Use Disorder (AUD) in the United States8.  The 
economic burden of this is estimated to be 249 billion dollars and approximately 88,000 
Americans die from alcohol-related causes each year9.  Untreated AUD is associated with an 
increased risk of accidents, injuries, suicide, and worsening of other health comorbidities10 and it 
is the fourth most preventable cause of death in the US9.  Treating addiction more effectively has 
become a priority of national importance and the Surgeon General has urged researchers to 
undertake testing of new treatments to combat addiction11.  The present study is intended to 
answer the call for accelerating drug development for AUD by exploring the potential to re-
purpose an existing drug as a treatment for AUD6-7.    
 
Rationale for developing lacosamide as an agent to treat AUD 
Lacosamide is a D-serine analogue that is approved for use as a therapeutic agent for treatment 
of partial seizures12.  In contrast to other anticonvulsant agents, this drug decreases seizure 
activity, in part, by enhancing slow sodium channel inactivation13-14.  The administration of 
lacosamide to either mice (C57Bl/6J) or rats (Long Evans) has been shown to significantly 
reduce their intake of alcohol in a model of ‘excessive’ drinking15.  This finding is of interest 
because the predominance of evidence suggests that in addition to its action on sodium channels, 
this anticonvulsant binds to and inhibits the activity of collapsin response mediator protein-2 
(CRMP-2)16-18.  Alcohol consumption in mice that had knockdown of CRMP-2 within the 
nucleus accumbens (a mesolimbic structure that regulates alcohol consumption and seeking 
behaviors) was decreased from levels seen in control animals15.  This finding implicates CRMP-
2 as having a role in the regulation of alcohol consumption. 
Based on the finding that lacosamide decreases alcohol consumption in rodents, we plan 
to test our hypothesis that this drug will have similar effects on the self-administration of alcohol 
by human subjects. Confirmation of this hypothesis would be of particular significance because 
CRMP-2 is a downstream target of the mammalian target of rapamycin complex 1 (mTORC1)15, 
19.  Several studies implicate mTORC1 in the development of the neuroadaptations that are 
involved in the seeking and consumption of a wide range of abused substances including 
alcohol26.   Administration of the mTORC1 antagonist rapamycin into the nucleus accumbens 
has been shown to decrease alcohol consumption and seeking behavior in rats21.  In addition, 
systemic and intra-amygdalar micro-infusion of this drug appears to disrupt memories of 
alcohol-related cues and thereby suppresses behavior in rodent models of drinking and relapse22.  
These results suggest that rapamycin or other drugs with similar mechanistic effects may have 
efficacy as medications for the treatment of AUD through a mechanism that is not targeted by 
any medications currently used to treat AUD.  
Rapamycin (sirolimus) is approved for use as an immunosuppressant agent, but it can 
produce toxic effects including myelosuppression and leukoencephalopathy which would 
constitute an unacceptable risk in an AUD population.  Testing of medications that act on targets 
downstream of mTORC1 that are less toxic than rapamycin may prove to be a useful approach in 
the development of drugs for the treatment of AUD through this novel mechanism. The findings 
of Liu and colleagues suggest that CRMP-2 may be an important downstream mTORC1 target 
for medications that will produce reductions in alcohol consumption because this protein may 
play a role in the neuroplastic changes associated with the development of excessive drinking. 
These changes may be related to alcohol-induced changes in the characteristics of neuronal 


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dendritic spines and related alterations in the activity of select neurotransmitter systems23-25.  Liu 
and his co-investigators reported that the mTORC1 antagonist rapamycin blocks alcohol 
mediated increases in CRMP-2 polysomal messenger RNA within the nucleus accumbens. 
Indeed, CRMP-2 protein levels within the nucleus accumbens of the rat have been found to be 
elevated after episodes of alcohol consumption.  CRMP-2 stabilizes microtubules within 
dendrites and may promote neurite outgrowth. Interestingly, lacosamide has been shown to block 
CRMP-2-induced neurite complexity in cultured brain cortical cells, suggesting a possible 
mechanism through which this medication may block alcohol-induced changes in 
neuroplasticity26.    
Lacosamide fits the description as a medication that modulates the activity of a 
downstream target protein of mTORC1 that appears to regulate alcohol consumption in rodent 
models.  In contrast to rapamycin, this drug has been found in clinical trials to be well tolerated, 
producing dose related adverse effects including dizziness, nausea, and diplopia that were in the 
mild to moderate range27 and that are common adverse effects produced by almost all 
anticonvulsant drugs. When used as monotherapy, a small percentage of patients had to 
discontinue lacosamide therapy because of the occurrence of rash, dizziness, headache, 
somnolence and elevations in liver function tests (i.e.γ-glutamyl transferase and aspartate 
aminotransferase)28.  There are two post-marketing reports of heart block occurring in patients 
who were treated with a combination of lacosamide and the beta-adrenergic receptor antagonist 
metoprolol29. Major concerns with the occurrence of severe skin rash, hepatoxicity, suppression 
of white blood cell production, or weight gain that are associated with the use of certain other 
anticonvulsant medications have not been reported to be a problem in patients treated with 
lacosamide. 
  
Treatment with the broad spectrum anticonvulsants topiramate and zonisamide, which are 
reported to reduce alcohol consumption in AUD subjects, is associated with the occurrence of 
deficits in cognitive functioning including impairment of verbal fluency and working memory30.  
These adverse cognitive effects may limit their acceptability for the treatment of AUD for many 
individuals.  The administration of lacosamide as compared to topiramate, when these drugs are 
used as adjunctive agents, may be less likely to adversely affect cognitive function in epilepsy 
patients31.  Lacosamide also appears to be less likely than the anticonvulsant carbamazepine to 
impair performance on a wide range of neuropsychological tests32.  In a study of the effects of 
lacosamide in patients with partial seizures, no significant differences in COWAT scores were 
found between weeks 1 and 28 of treatment with this drug when administered in doses ranging 
between 100 to 400 mg per day33.  Lacosamide was found to produce a significant, but modest, 
reduction in WAIS-III Digit Span scores (a test of working memory) collected for these patients. 
We believe that lacosamide is a promising agent for drug development given the novel 
mechanism of action, positive findings in animal models, and an acceptable safety profile.  
In this study, the effects of lacosamide on cravings will also be assessed. This is 
important because cravings that follow alcohol consumption may be important factors in 
motivating drinking34-36.  The effects of anticonvulsants on these factors in the context of alcohol 
challenge and self-administration studies have not been extensively examined. In an alcohol self-
administration study testing zonisamide, we found that reductions in craving occurred in 
association with reduced alcohol self-administration37.  These results are similar to those 
showing that naltrexone administration leads to significant corresponding reductions in alcohol 
self-administration and craving scores38.  Understanding the effect of lacosamide on craving and 
stimulant effects of alcohol may inform our understanding of how lacosamide impacts drinking.   


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This study will be conducted in compliance with the protocol, applicable regulatory 
requirements, and BMC/BU Medical Campus Human Research Protection policies and 
procedures. 
 
3.2 
Rationale and Purpose  
 
This study holds significant innovation as there is mounting evidence that medications that act on 
targets downstream of mTORC1 have the potential to decrease craving and consumption, but no 
medications have been developed to date to take advantage of this novel mechanistic approach.  
Two medications which impact the mTORC1 pathway, lacosamide and rapamycin, have been 
tested in rodent models and both medications have been shown to reduce alcohol 
consumption15,21.  Rapamycin is not a promising candidate for drug development due to the 
potential for serious adverse effects, but lacosamide is promising given the findings from animal 
models, the tolerable safety profile, and the low incidence of cognitive adverse effects relative to 
other anticonvulsants used to treat AUD.  To date, there have been no controlled studies testing 
lacosamide in human drinkers that either have been published or registered with 
Clinicaltrials.gov. The study answers the call for accelerating the development of medications for 
AUD by testing a commercially-available and well-tolerated agent at a fraction of the cost of 
developing novel therapies.  If successful, this study could lead to a phase II randomized 
controlled trial to test lacosamide as a treatment for AUD.   
 
4 
Objectives 
 
4.1 
Study Objectives 
 
The specific objective of this study is to determine whether lacosamide has effects on alcohol 
craving and consumption.  This medication is a promising candidate that has unique actions on 
voltage-gated sodium channels and may have inhibitory effects on collapsin response mediator 
protein-2 (CRMP-2).  Testing the effects of lacosamide on drinking is a compelling opportunity 
that is consistent with the mission of NIAAA to evaluate the efficacy of re-purposed compounds 
with novel mechanisms that have the potential to treat AUD.   
4.2 
Study Outcome Measures 
 
4.2.1 
Primary Outcome Measures 
 
The primary outcomes are alcohol consumption and cravings during the alcohol self-
administration trials.  Drinking volume during the alcohol self-administration will be measured 
to evaluate the effects of lacosamide vs. placebo on the rate of alcohol consumption after a 
priming drink.  Alcohol craving will be measured using the Visual Analog Scale (VAS) and the 
Alcohol Urge Questionnaire (AUQ)39 during the lacosamide self-administration trial.  These self-
report measures of craving will be used to evaluate the effect of lacosamide on craving vs. 
placebo.   
 
4.2.2 
Secondary Outcome Measures 
 
Secondary outcome measures for this study include the effect of lacosamide on 1) cognitive 


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function, and 2) alcohol use and craving during the titration period. The Controlled Word 
Association (COWAT)40 and the Wechsler Adult Intelligence Scale (WAIS-5)41 Spatial and 
Digit Span tests will be used to assess the effects of lacosamide administration on cognitive 
function. The Obsessive-Compulsive Drinking Scale (OCDS)42, and the alcohol VAS will be 
used to assess the effects of lacosamide on craving during the medication titration period.   
 
 
5 
Study Design 
 
This is a double-blind, randomized, placebo-controlled, crossover design trial that will test the 
effect of lacosamide on alcohol self-administration and craving following a priming dose of 
alcohol.  An established human laboratory self-administration procedure will be followed38. The 
O’Malley self-administration procedure entails the administration of a priming drink followed by 
the presentation of four drinks on a tray which subjects may drink, or receive compensation for 
the drinks not consumed. After one hour the first tray of drinks is removed and subjects are then 
given the opportunity to consume a second tray of drinks. Confirmation of the validity of this 
approach as a method for screening for medications to treat AUD include the finding that pre-
treatment with naltrexone, which is an approved medication for treating AUD, significantly 
reduced alcohol consumption when the O’Malley self-administration procedure was used45.  
Using this procedure, our group has found that the anticonvulsant zonisamide reduces alcohol 
consumption in non-treatment seeking social drinkers43.  We later confirmed that the 
administration of zonisamide decreases alcohol consumption in subjects with AUD in a double-
blind randomized clinical trial25 as have other investigators43.  Testing lacosamide using 
O’Malley’s self-administration procedure is the next logical step in drug development following 
positive findings that lacosamide reduces drinking in animal models.  The human laboratory-
based alcohol self-administration procedure is a cost effective and time-efficient method for 
testing novel drug candidates for AUD treatment6.  
 
Subjects: Heavy-drinking subjects will be enrolled to increase the potential generalizability of 
these findings to a clinical AUD population.  Subjects will be recruited through radio 
advertisements, newspaper advertisements, internet advertisements, study flyers, internet 
postings, and an established subject registry at Boston Medical Center.  Interested subjects will 
be screened by telephone to determine initial eligibility prior to the baseline assessment.  
   
 
6 
Potential Risks and Benefits 
 
6.1 
Risks 
Risks of study medication (see product insert) 
To minimize the risk of adverse health events we will instruct subjects to contact study staff with 
any questions or concerns about changes in health effects after initiating study 
medication/placebo. Trained medical staff will evaluate any reported adverse effects and make a 
clinical determination about management through dosing methods (e.g., taking before bedtime or 
with food), dose discontinuation, and/or referral for medical care. Subjects will be given a wallet 
card that includes a phone number with 24/7 coverage for medical emergencies. As an added 


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safety precaution, subjects will be contacted mid-week of the titration period for an adverse 
effect assessment.    
 
Adverse effects 
Treatment emergent adverse events (TEAs) in studies of the effects of lacosamide are shown in 
the three tables below. Of most relevance to this protocol are findings from the TEAs in healthy 
subjects shown in Table 1.  The least tolerated dose reported for healthy subjects was found in a 
study that subjects that received 400 mg per day of lacosamide for 6 days without a period of 
drug titration44.  Roughly 8% of subjects in this study reported feeling drunk at this dose.  
 
Table 1. Common TEAs for healthy subjects obtained in 3 studies 
TEA 
Healthy (n=20)45 
Healthy (n=50)46 
Healthy (n=56)44 
Healthy (n=54)44 
 
300mg 
300 mg 
400 mg 
Placebo 
 
6 Weeks 
21 Days 
6 days 
6 days 
 
3 Week Titration 3 Week Titration No Titration 
No Titration 
Dizziness 
2% 
7.4% 
10.0% 
6.5% 
Somnolence 
4.0% 
11.1% 
Not Reported 
Not reported 
Headache 
10.0% 
11.1% 
16.7% 
14.5% 
Nausea 
4.0% 
Not reported 
8.3% 
1.6% 
 
Data from seizure patients who received lacosamide as monotherapy is presented in Table 247.  
At the 300 mg dose these patients showed a greater incidence of dizziness, nausea, and headache 
than did healthy subjects treated with this dose. Data from the monotherapy study also includes 
findings from when subjects were also receiving other anticonvulsant medications.  
 
 
Table 2. Findings for lacosamide monotherapy studies.   
TEA 
Monotherapy47 
Monotherapy 
Monotherapy Newly 
Diagnosed Subjects48 
 
300mg  
400 mg 
200-400 mg/day 
 
N=106 
N=319 
N=444 
Dizziness 
17.9 
26.0 
12% 
Somnolence 
14.2 
9.1 
5% 
Headache 
17.9 
13.2 
14% 
Nausea 
12.3 
13.8 
6% 
Blurred 
Vision 
5.7 
6 
Not reported 
 
Table 3 includes data from seizure patients treated with lacosamide in combination with other 
anticonvulsant drugs during the titration phase for lacosamide.  
 
Table 3. Pooled percent common TEAs for focal seizure patients treated with lacosamide as an adjunctive 
medication obtained for the titration phase of 3 RCT’s.49  


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TEA 
200 mg (n=270) 
400 mg (n=471) 
Placebo (n=364) 
Dizziness 
10.4 
24.6 
6.6 
Fatigue 
6.7 
6.8 
5.2 
Ataxia 
2.2 
5.9 
1.4 
Balance Disorder 
0.7 
3.6 
0.0 
Nausea 
5.6 
8.5 
3.6 
Blurred Vision 
1.9 
6.2 
1.6 
Diplopla 
4.4 
8.3 
1.1 
Risks of Dizziness. Ataxia, Somnolence, and Incoordination 
Data presented in the tables shown above suggest that there may an increased risk of 
dizziness,ataxia, somnolence, and incoordination associated with the administration of 
lacosamide to healthy subjects. Consequently, subjects in this study will be counseled that the 
administration of lacosamide may produce dizziness, double vision, somnolence, and problems 
with balance and coordination. They be advised to avoid driving, operating complex machinery, 
or engaging in other hazardous activities until they have become familiar with the effects of 
lacosamide.   
Physical discomforts: 
The drawing of blood may cause pain, bruising, lightheadedness, and on rare occasions, 
infection. Subjects may briefly feel the prick of the needle when it is inserted.  Subjects may feel 
dizzy or faint when blood is drawn. Trained phlebotomists will be used to minimize these risks.    
ECGs may cause discomfort and/or irritation of the skin (redness and itching) from the adhesive 
electrodes. Hair on your chest may need to be removed in order to obtain the best electrical 
contact between the adhesive electrodes and subjects’ skin. Trained staff will be used to 
minimize these risks. 
Cardiac Risks 
A dose dependent prolongation of the PR interval has been observed in both patients and healthy 
subjects who have received lacosamide. Asymptomatic atrioventricular (AV) block has been 
observed in clinical trials in 0.4% of patients being treated for seizures and 0.5% of patients 
being treated for diabetic neuropathy. Cases of second degree and complete atrioventricular 
block have been seen in both seizure and pain patients. In two postmarketing reports, third 
degree AV block was observed in patients who had a significant cardiac history and were being 
treated the beta blocking drug metoprolol and the calcium channel blocker amlodipine when 
receiving infusions of lacosamide at above the recommended doses for this drug. Bradycardia 
also has been observed in patients who have received intravenous infusions of lacosamide.   
No cases of atrial fibrillation or flutter were observed in the short-term investigational trials of 
lacosamide seizure patients. Cases of atrial fibrillation and atrial flutter, however, have been 
detected in both open label epilepsy trials and in postmarketing experience.  In patients who had  
diabetic neuropathy, 0.5% of patients had episodes of atrial fibrillation or atrial flutter while no 
episodes of these disorders occurred in placebo-treated patients. 
It is recommended that lacosamide be used with caution in patients with previously identified 
conduction problems including  marked first-degree AV block, second-degree or higher AV 


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block and sick sinus syndrome without pacemaker), sodium channelopathies, a history of 
myocardial infarction or congestive heart failure. Its use should be avoided in individuals who 
are receiving other medications that may prolong the PR interval. 
To minimize the risk of cardiac adverse events, the published caution guidelines will be used to 
exclude patients from entering this study. All study candidates will receive an ECG to detect 
disturbances in cardiac function that may place them at risk for a cardiac conduction problem if 
they were to receive lacosamide. Patients will be excluded if either the results of the ECG 
recording or their medical history indicates that they would be at risk of developing cardiac 
problems from lacosamide use. Study candidates will also be excluded from study entry if they 
are taking any medication that may block cardiac conduction. This will include the use of any 
antiarrhymic agents including beta and calcium channels blockers and digoxin.  
Psychiatric risks 
In clinical  trials of the effects of antiepileptic drugs (AED), the incidence of suicidal behavior or 
ideation  was 0.43% in AED-treated-subjects versus  0.24% for  placebo-treated patients, 
representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 
treated patients. These trials included 27,863 patients being with AED and 16,029 patients to 
who placebo was administered. There were four suicides in drug-treated patients in these trials 
and none in the placebo-treated patients. Because of these finding treatment with any 
anticonvulsant medication including lacosamide must be considered to produce to an increased 
risk of suicidal thoughts and behaviors.   
To minimize the risk of worsening suicidal thoughts and behaviors we will screen for suicidality 
using the Columbia-Suicide Severity Rating Scale and the MINI Neuropsychiatric Interview.  
Subjects with a MINI suicidality score greater than 8 (low risk) will be excluded.  Subjects who 
report any active suicidal thoughts or behavior as measured the C-SSRS will be excluded from 
participation.  In addition to excluding active suicidality, the MINI will be used to rule out 
subjects who have psychiatric conditions that may increase the risk of the occurrence of suicidal 
thoughts or behavior (e.g., major depression, bipolar disorder).  Assessment and scoring of 
suicide rating scales will be conducted in real-time while the subject is present.  Suicidality will 
be assessed by trained clinical staff including study MDs, a psychologist, a nurse, and a mental 
health counselor.  If subjects are found to be at risk for self harm, study staff will work with the 
subject to develop a safety plan that could include escorting the subject to the BMC ED or 
calling BEST.  To minimize the risk of abuse of lacosamide, subjects with lifetime substance use 
disorders will be excluded (with the exception of marijuana, caffeine, nicotine and alcohol).  To 
date, there are no published reports of the abuse of lacosamide. 
Risk to a developing fetus 
The administration of lacosamide to pregnant rats has been found to produced developmental 
toxicity that included increased embryofetal and perinatal mortality, and growth deficits. 
following administration during pregnancy.  Neurotoxicity has been seen in rats who received 
this drug  during a period of postnatal development believe to correspond to the third trimester of 
human pregnancy. 
To protect against the risk of potential developmental toxicity to a fetus, women will be excluded 
from study entry if they have a positive urine pregnancy test or if they are of childbearing age 
and are either not using appropriate methods of contraception or not practicing abstinence. Urine 


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pregnancy testing will also be completed at each study visit as a protection to the developing 
fetus.  Subjects with positive pregnancy test results will be discontinued form participation 
Risk of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ 
Hypersensitivity 
During the clinical development of lacosamide one case of symptomatic hepatitis and nephritis 
was observed among 4011 subjects exposed to this drug. This happened in a healthy volunteer, 
10 days after the discontinuation of lacosamide. This case was deemed to be consistent with a 
delayed multi-organ hypersensitivity reaction. Other possible cases included two subjects who 
had a rash and elevated liver enzymes and one subject who had myocarditis and hepatitis of 
uncertain etiology. We ask that subjects contact a study physician immediately if they develop a 
rash, fever, become excessively tired, notice that their urine turns brown, or notice your skin 
turning yellow.   
Risk of Stevens Johnson Syndrome /Toxic Epidermal Necrolysis 
Post-marketing data indicate the occurrence of cases of Stevens Johnson Syndrome and Toxic 
Epidermal Necrolysis in patients being treated with lacosamide. This data does not allow for 
determination of a reliable estimate of  frequency of occurrence these disorders being treated 
with lacosamide nor do they establish a causal relationship between appearance of these 
disorders and exposure to this anticonvulsant. Subjects will be asked to contact a study physician 
immediately if they develop a rash, fever, sore throat, mouth ulcers, or bruising while taking the 
study medication. 
Risks of alcohol self-administration 
 
Risk to recovery efforts 
Treatment-seeking drinkers will be excluded from this study to minimize the risk that drinking in 
the laboratory could worsen outcomes for a subject trying to reduce or abstain from alcohol. All 
subjects will undergo a medical screening and we will exclude subjects who have a medical or 
mental condition for which alcohol exposure in this study would be contraindicated.  All subjects 
will receive the NIAAA self-help guide Rethinking Drinking at the end of study participation.  
Risk of overconsumption  
To minimize the risk of subjects reaching a level of intoxication that is uncomfortable to them, 
we will remind subjects that they may discontinue study participation at any time.  Subjects will 
be asked to drink to a target BAL (.03 g/dl) that is customary for them given the minimum 
drinking criteria.  The alcohol self-administration paradigm that we have chosen does not include 
any coercion, inducements, or pressure to consume more alcohol than subjects feel comfortable 
consuming.  There are no experimental manipulations that would increase drinking (e.g., heavy 
drinking confederate, anxiety manipulation).  In fact, in this study design there are inducements 
for subjects to not drink beyond the initial priming dose.  Subjects will receive monetary 
incentives for each drink that they do not consume.  Access to medical backup services will be 
maintained throughout each alcohol challenge session.  Subjects will be monitored during the 
course of the study, both through direct assessment with study staff and by observation through a 
video camera.  Medical staff will evaluate subjects and may make a determination to halt study 


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participation if the subject becomes too behaviorally impaired or if there are emergent safety 
issues.  Subjects who have a BAL greater than .04 g/dl or who appear to be too behaviorally 
impaired to leave our research center will be asked to remain in the clinic until their intoxication 
is reduced to a level that it is safe to discharge them from the research laboratory. BAL readings 
will be taken twice to confirm BAL is not greater than .04 g/dl prior to release.  Subjects will not 
be released within 60 minutes of their last drink consumed to ensure that peak BAC has been 
reached prior to discharge.  During the descending BAL period, subjects will have access to a 
comfortable space with entertainment (streaming media), snacks, non-alcoholic beverages, and a 
nearby bathroom.       
Risk of loss of confidentiality  
There is some risk that health information collected as part of this study could be seen by 
unauthorized individuals.  Every effort will be made to minimize this risk and protect subject 
confidentiality.  Electronic data will be housed in the REDCap data management system.  
REDCap is protected via Secure Sockets Layer (SSL) encryption that provides access restriction 
options.  Exported data from REDCap will be stored on a secure password-protected server 
behind the BMC firewall. Source and CRF binders will be stored in a double-locked area that is 
accessible to only study staff.  Subjects will be assigned a study identification number and this 
will be used to code any forms that do not require the subject’s direct identifiers (e.g., consent 
form, laboratory results, and contact information).  A linking key that associates study ID with 
direct identifiers will be stored in a double-locked cabinet accessible only by study team 
members.  Data will be stored on a password-protected computer accessible only to the study 
team.  Video of subjects during the drinking session will be stored on an encrypted drive with 
password protection.  Video files will be deleted at the end of the study.  All study staff will 
receive appropriate training for the protection of human subjects (NIH Protecting Human 
Research Participants, CITI Training). A certificate of confidentiality will be sought to protect 
subjects from disclosure under court order or subpoena.  
 
6.2 
Potential Benefits 
 
There is no potential direct benefit to participation in this study.  This study presents a very 
strong potential for benefit to science.  Drug development for treating AUD is costly and few 
pharmaceutical companies are testing novel compounds as agents to treat AUD.  Re-purposing 
compounds with FDA approval for other indications is the most promising route for rapid and 
cost-effective development of medications to treat AUD.   This study will bridge the gap in drug 
development by providing a test of lacosamide to see if it may be a candidate drug for treating 
AUD.  If successful, this could lead to the expansion of pharmacotherapy options to treat AUD 
and a broadening of our understanding of the mechanistic approach to treating AUD.  
 
6.3 
Analysis of Risks in Relation to Benefits 
 
Given that lacosamide has FDA approval for another indication and is well-tolerated in other 
populations, the risk of this medication to human subjects has been established through pre- and 
post-marketing data. With the protections we have in place for all the potential risks in this study, 
we believe the risks of this study are well minimized.  The study holds significant promise for 


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informing new models of care given the novel mechanism of lacosamide.  We believe the 
risk/benefit ratio is favorable. 
 
7 
Study Subject Selection 
 
7.1 
Subject Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
inclusion criteria: 
1.  21-55 years of age 
2.  Can provide proof of age with state-issued or federal picture ID 
3.  Exceeds safe weekly drinking limits (≥14 drinks for women or ≥21 drinks for men per week) 
4.  Reports at least an average of one episode per week of binge drinking (>3 for women, >4 in 
the four weeks prior to baseline screening 
5.  Meets DSM-5 criteria for mild alcohol use disorder or greater severity.  
6.  Have a smartphone to complete some of the study assessments.      
 
7.2 
Subject Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
 
1.  Currently seeking treatment for alcohol problems  
2.  Clinical Institute Withdrawal Assessment at >10  
3.  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 
4.  If female, pregnant, nursing, or have plans to become pregnant 
5.  If female, does not agree to use an accepted form of birth control 
6.  Is currently using medications for which alcohol is a contraindication 
7.  Has a medical or mental health condition for which further alcohol exposure at the planned 
dose range would be contraindicated. 
8.  Current risk of suicidality (MINI suicidality score greater than 8 (low risk) or Yes to the 
ideation question #4 of the C-SSRS) 
9.  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. 
11.  Has previous exposure to lacosamide 
12.  Has received any form of counseling, self-help, pharmacotherapy, or other  
intervention to treat AUD in the past 90 days. 
13.  Is unwilling to suspend use of multivitamins that contain riboflavin during study 
participation 
14.  Has urine toxicology results positive for cocaine, opioids, amphetamines, buprenorphine, 
methadone, or methamphetamines  
15.  Liver function values AST or ALT are twice the normal limit 
16.  GFR <80 mL/min   
17.  Unable to comfortably abstain from nicotine for a period of 8 hours.   
 


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8 
Study Intervention 
Study Medication 
Study medication will be purchased and packaged by the BMC Investigational Pharmacy 
Service.  Lacosamide (100mg and 150mg tablets) will be over-encapsulated with 50mg of 
riboflavin which will serve as a tracer of medication compliance.  Matching placebo will also be 
packaged using lactose and 50mg of riboflavin.  Medication will be dispensed to each subject in 
two bottles: 1) 11 pills of Lacosamide (100mg) or placebo 2) 3 pills of lacosamide 150mg or 
placebo. Capsule size required will be determined by IPS with the goal of a minimum capsule 
size needed for over-encapsulation. If a subject reports losing (or destroying) study medication, a 
replacement prescription will be written by one of the study physicians and the BMC 
Investigational Pharmacy will dispense additional medication to replace the lost (or destroyed) 
medicine.  
 
Dosing 
Subjects will take a single 100mg capsule in the evening of randomization day.  Subjects will 
take 100 mg of lacosamide (or placebo) twice per day from day 2 through day 6.  On day 7 
subjects will increase to 150mg twice daily.  Based on the metabolism of this drug, we expect to 
be within range of 90% of steady state for a 300 mg daily lacosamide dose by day 8 when the 
alcohol challenge trial will occur which is consistent with the clinical dose range (300-400mg 
daily as monotherapy) of this drug when it is used for seizure disorders55.  Subjects who are 
unable to tolerate the titration period will be discontinued from the study.   
 
 
Dose Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Self-
Admin 
AM 
  
100mg 100mg 100mg 100mg 100mg 150mg 150mg 
PM 
100mg 100mg 100mg 100mg 100mg 100mg 150mg   
 
Medication Storage 
Medication will be stored in the Investigational Pharmacy at room temperature (within the range 
of 59°F to 86°F) in a secured area until the time that medication is needed for study subjects.  
Stability and expiry will be monitored by IPS according to the labelling of the medication from 
the manufacturer.   
 
Medication Labeling 
The study number will be preprinted on each bottle label. The label will include the drug name 
(e.g., Lacosamide XXXmg or placebo”).  The label will also have a randomization number, the 
number of tablets contained in the bottle, storage conditions, the 24/7 phone number of the 
clinical site, and places to record the subject number and the date dispensed.  Additional fields 
may be added to this label to meet any regulatory requirements as determined by IPS.   
 
Medication Blinding and Unblinding 
Study medication and placebo capsules will be identically matched in appearance and the bottle 
labels will not reveal the drug identity. The Study PI and study physician(s) will make the 
decision to un-blind the identity of the study medication in the event that the study blind needs to 


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be broken to make medical decisions regarding subject treatment. 
 
Medication accountability 
The site principal investigator (PI) or designated study personnel will maintain a log of all study 
medication and record of dispensing of all medication to the subject. The site PI or his staff will 
count the tablets remaining at the end of the study and record the tablet count on the appropriate 
drug accountability form. Subject compliance with study medication will be assessed by 
comparing unused capsule count to dispensing logs and dosing records (number of tablets 
dispensed, number of tablets prescribed, versus the number returned). Subjects will also be asked 
to account for any missing tablets. If the bottle is not returned, the subject will be asked to report 
daily drug self-administration. 
 
9 
Study Procedures 
Study Overview: Each subject will complete 5 clinic visits over a period of up to 44 days of 
participation.  Study participation is comprised of a baseline assessment, randomization visit, 
alcohol self administration Trial 1, an assessment visit to verify continued eligibility and 
dispense medication, and a second alcohol self-administration Trial (see figure 1 for an overview 
of study participation).     
 
Baseline assessment:  Consenting subjects will undergo a general 
medical screen, physical examination, and electrocardiogram.  Drinking 
will be assessed using the TLFB50, alcohol withdrawal using the Clinical 
Institute Withdrawal Assessment51, and suicidality using the Columbia-
Suicide Severity Rating Scale (C-SSRS)52.  Exclusionary mental health 
conditions will be assessed using the MINI Neuropsychiatric Interview 
for DSM-553.  Subjects will undergo laboratory testing that includes liver 
function, electrolytes, blood chemistries, urine analysis, urine toxicology 
and a urine pregnancy test for women of child bearing age.  
 
Study randomization (medication visit #1): Qualified subjects will return 
to the clinic within 14 days for randomization to a crossover sequence of 
drug exposure.  Subjects will be assigned to one of 2 groups , with one 
group receiving lacosamide prior to the first alcohol challenge trial and 
the other receiving lacosamide prior to the second alcohol challenge trial.  
Randomization of subjects will be accomplished using a stratified 
randomization procedure that will allow for between-group balance for drinking 
status (heavy vs. very heavy).  Heavy drinking is defined as ≥ 21 and < 35 
standard drinks per week for men, and ≥ 14 and < 28 standard drinks per week 
for women.  Very heavy drinking is defined as ≥ 35 standard drinks per week 
for men, and ≥ 28 standard drinks per week for women.  This stratified 
randomization will minimize the possibility that the order of treatment 
administration seems to influence outcomes when order effects are actually related to differences 
in severity of drinking between the two groups of subjects who are receiving the treatments in a 
different order. On the day of randomization, subjects will undergo an alcohol breath test, urine 
drug screening, assessment of concomitant medications, assessment of cravings, and drinking.  
Subjects who have purposefully abstained from drinking and achieved 7 days of abstinence prior 


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to the challenge will be excluded from participation for ethical reasons55.   
 
 
Titration period: 
Randomized subjects will receive 8 days of study medication at the time of randomization.  A 
riboflavin tracer (50mg) will be added to each capsule to serve as an objective measure of 
medication adherence on the day of the alcohol challenge56. Two bottles will be dispensed to 
each subject: 1) 11 pills of Lacosamide or placebo over-encapsulated with 50mg of riboflavin 
and 2) 3 Pills of lacosamide or placebo over-encapsulated with 50mg of riboflavin.  Subjects will 
take 100 mg of lacosamide (or placebo) twice per day until day 7.  On day 7 subjects will 
increase to 150mg twice daily.  Based on the metabolism of this drug, we expect to be within 
range of 90% of steady state for a 300 mg daily lacosamide dose by day 8 when the alcohol 
challenge trial will occur which is consistent with the clinical dose range (300-400mg daily as 
monotherapy) of this drug when it is used for seizure disorders57. Subjects who are not able to 
achieve the target dose due to adverse effects will be discontinued from the study.   
 
 
Dose Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Self-
Admin 
AM 
  
100mg 100mg 100mg 100mg 100mg 150mg 150mg 
PM 
100mg 100mg 100mg 100mg 100mg 100mg 150mg   
 
The seven-day period of medication titration will begin within a window of 6 days depending 
upon scheduling the alcohol challenge.  Subjects may be randomized and instructed to start the 
medication up to 6 days later so that day 8 will conicide with the alcohol challenge appointment.  
Subjects will be given a brief phone reminder to start medication on Day 1.  During the seven-
day period of medication titration, subjects will be asked to answer a medication compliance 
question each day by smartphone using the REDCap data capture through a web-based portal58.  
In addition to assessing medication compliance, subjects will also be asked to rate their craving 
for alcohol each day using the alcohol VAS. Subjects will receive a $5 reimbursement on each 
day they complete the VAS and answer the medication compliance question using the REDcap 
web-based portal.  Subjects will be contacted by telephone on day 3 of the medication titration 
period for an adverse event assessment.     
Medication Visit #2 
After the 7-10 day washout period subjects will return to the lab to receive study medication 
prior to the alcohol challenge #2.  Subjects will complete the same tests and interviews 
completed during the randomization visit (See appendix A for schedule of events).  Based on the 
assessments at medication visit #2, subjects be discontinued for the following reasons: 
pregnancy, recreational drug use, evidence of non-compliance with study medication, suicidal 
thoughts or behavior, and use of a new medication that would make participation unsafe.  
Subjects will receive an 8-day supply of study medication and will be scheduled for the alcohol 
challenge #2.   
Alcohol Challenge Trials 1 & 2:  Subjects will return to the laboratory on day 8 of titration for 
each medication trial  to complete the alcohol challenge.  For safety reasons, subjects will be 
asked to arrange transportation plans (no driving) prior each of the alcohol challenge trials.  


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Figure 2: Alcohol Self-Administration Procedure 
 Priming Dose 
5 minutes  
Drink mixed to 
achieve BAL= 
0.03g/dl 
Observation  
40 minutes 
Craving and 
intoxication 
measured in 10-
minute intervals 
Self-Administration 
Blocks 1 & 2 
60 minutes each 
4 drinks per block 
Each drink mixed to 
raise BAL 0.015 g/dl 
There will be a 7-10 day washout period between alcohol challenge Trial 1 and medication visit 
2. Based on the known half-life of lacosamide, all of the medication will be cleared within 7 
days.  The washout may extend to 10 days to accommodate the scheduling of Trial 2. 
Concomitant medications, urine drug screening, urine pregnancy testing, blood alcohol level will 
be assessed to determine eligibility to proceed with the challenge.  Blood alcohol level must be 
0.000 to continue with the study procedures.  Urine collected for drug screening will be exposed 
to ultraviolet light as an objective test of medication compliance.  If no fluorescence is observed 
in the urine sample the subject will be excluded from continuing with the challenge.  Measures 
of drinking (TLFB), cravings, (OCDS and AUQ), and neurocognitive function (COWAT, 
WMSIII Spatial Span and Digit Span tests) will be collected to inform secondary outcomes.  
Subjects will be observed taking the morning dose of lacosamide (or placebo) on the day of the 
challenge (after compliance is confirmed via a urine screening).  The peak plasma concentration 
of lacosamide should be reached approximately 60 minutes after administration.  The alcohol 
self-administration session will begin no sooner than one hour after the administration of the 
observed 150mg morning dose. The alcohol self-administration will be conducted in the GCRU.  
The room will be a carpeted and furnished with a lounge chair, side table and television which 
allows access to popular streaming entertainment (e.g., Netflix, YouTube). A small unobtrusive 
camera is mounted in one corner to allow for monitoring without study staff being present in the 
room. The room has ready access to a bathroom.  The alcohol self-administration is divided into 
four segments: 1) a 5-minute segment for the priming dose, 2) a 40-minute segment for 
observing alcohol’s effects, 3) a 60-minute segment of alcohol self-administration (Block1) and, 
4) a second 60-minute segment of alcohol self-administration (Block2) [see figure 2 for the 
alcohol self-administration Procedure].   
 
Priming dose.  Subjects will be given a 
priming drink designed to increase the 
subject’s blood alcohol level (BAL) to 
0.03g/dl, using the alcohol of their 
choice that is 24% Alcohol By Volume 
(ABV) or greater.  The volume of 
alcohol will be calculated using an online 
tool developed by UW-Madison (http://dionysus.psych.wisc.edu/WebCMS/baccalc.htm) based on a 
formula described by Watson59 The subjects will be asked to drink the priming drink over a period of 5 
minutes. Part of the purpose of the priming drink is to normalize drinking in the laboratory.  
 
Observation period. Subjects will be observed for 40 minutes following the priming dose of 
alcohol to allow for absorption of the alcohol. 
 
Alcohol self administration Blocks 1 and 2.  In each of the alcohol self-administration Blocks, 
subjects will be presented with four drinks, each mixed to raise their BAL 0.015g/dl. They will 
be told that they can either consume the desired number of drinks over the following 60 minutes 
or they will receive the equivalent dollar amount of the cost of each drink ($3.00) they did not 
consume before leaving the clinic. At the end of each 1 hour session the tray with the remaining 
drinks will be removed and the amount of alcohol remaining will be measured.  Cravings will be 


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assessed using the AUQ and VAS every 30 min during the self-administration blocks. Based on 
the rate of alcohol metabolism over the time of the trial, we anticipate that subjects who 
consumed every drink could reach a BAC of .09 to .13 g/dl depending upon differences in 
alcohol metobolism.  Safety assessments will be completed (intoxication, sedation, adverse 
effects) prior to subjects leaving the laboratory. Subjects will be required to have a plan for 
transportation home that does not involve driving.  Subjects will not be released until their blood 
alcohol level is ≤ 0.04 g/dl and they are not behaviorally impaired.  After the second alcohol self-
administration trial has been completed subjects will receive a copy of the NIAAA publication 
Rethinking Drinking60 and will be encouraged to review rethinking drinking materials online.   
 
Subject compensation 
Subjects will be compensated up to $418 for completion of all study activities.  Subjects will 
receive a reimbursement of $40 for the screening visit, $20 for the randomization visit and $20 
for the assessment visit prior to Trial 2.  Subjects will receive $80 for each of the two alcohol 
challenge trials and a $40 completion bonus if they complete both challenges.  Subjects will 
receive a $5 payment each on day during the two 7-day titration periods that they respond to the 
REDcap survey to rate their alcohol craving and report their medication compliance. Subjects 
will also receive a $10 completion bonus if they complete the craving scale and medication log 
on all seven days. Subjects may receive up to $48 dollars in payments for drinks not consumed 
during the two alcohol self-administration Trials.   
 
In addition to this $418 of compensation, subject may also be reimbursed up to an additional 
$60 for distributing study recruitment materials to other people who may want to take part in 
this study.  Distributing recruitment materials is completely optional.  subjects may take part in 
the study and decline to hand out flyers to people they know.   
 
Subjects who report no recreational drug use other than marijuana at the time of phone screening 
but then test positive for recreational drug use other than marijuana at the first in-clinic visit will 
not be reimbursed.  Subjects will be informed of this policy at the time of telephone screening.  
This measure is in place to prevent subjects from lying about no recreational drug use in order to 
receive compensation for a single visit in this study.   
 
10 Assessment of Safety and Data Safety Monitoring Plan (DSMP) 
 
10.1 
Definitions 
 
The following definitions will be used in the assessment of safety: 
 
Adverse Event (AE) is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research. 
 
Serious Adverse Event (SAE) is any adverse event that  
(1) results in death; 


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(2) is life-threatening; 
(3) results in inpatient hospitalization or prolongation of existing hospitalization; 
(4) results in a persistent or significant disability/incapacity; 
(5) results in a congenital anomaly/birth defect; or 
(6) based upon appropriate medical judgment, may jeopardize the subject's health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition (examples of such events include allergic bronchospasm requiring intensive 
treatment in the emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse).  
 
Life-threatening means that the event places the subject at immediate risk of death from the 
event as it occurred.  
 
Unanticipated Problem is defined as an event, experience or outcome that meets all three of the 
following criteria:  
 
is unexpected; AND 
 
is related or possibly related to participation in the research; AND 
 
suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.  
 
Possibly related means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research 
 
Unexpected means the nature, severity, or frequency of the event is not consistent with either: 
 the known or foreseeable risk of adverse events associated with the procedures involved in 
the research that are described in (a) the protocol–related documents, such as the IRB-
approved research protocol, any applicable investigator brochure, and the current IRB-
approved informed consent document, and (b) other relevant sources of information, such 
as product labeling and package inserts; or 
 the expected natural progression of any underlying disease, disorder, or condition of the 
subject(s) experiencing the adverse event and the subject’s predisposing risk factor profile 
for the adverse event. 
 
10.2 
Safety Review 
 
Both the risks listed in Section 6.1 and unknown risks will be monitored as follows:  
 
Adverse events will be monitored from the time of study enrollment until the end of 
participation.  Adverse events will be monitored by medical staff using the “adverse events” 
CRF.  Adverse event monitoring will be conducted at a mid-week call during both titration 
periods.  Adverse events will also be assessed on the alcohol self-administration challenge days.  
Subjects will be given a wallet card with a 24/7 telephone number in the event that there are 
adverse effects which the subject would like to consult with medical staff prior to the next 
scheduled visit.  Adverse events will be assessed if at any point in the study a subject uses this 


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24/7 emergency phone contact. If a subject has an ongoing SAE or unanticipated problem at the 
time that the subject completes all study procedures, Adverse Event assessment will continue 
until satisfactory resolution (either resolved or stabilized and is not expected to resolve in the 
near term) of the event or problem. 
 
For each recorded AE or SAE, the study MD staff or study nurse will assess expectedness based 
on the known published side effect profile for lacosamide.  The study MD staff or study nurse 
will also assess severity based on the following criteria: 
Mild: 
An event that is usually transient, requiring no special treatment, and does 
not generally interfere with the subject’s daily activities. 
Moderate: 
An event that interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the 
subject. The event is usually ameliorated with additional specific 
therapeutic intervention.  
Severe: 
 
An event that interrupts usual activities of daily living or significantly 
affects clinical status. The event poses a significant risk of harm to the 
subject and hospitalization may be required, and typically requires 
intensive therapeutic intervention. 
Life-threatening 
An event that puts the subject into imminent risk of death without intervention. 
 
The study MD staff or study nurse will assess AE/SAE relationship to the investigational product 
based on the following criteria: 
 
Unrelated: 
The subject did not receive the investigational product, the temporal sequence 
of the AE/SAE onset relative to administration of the investigational product 
is not reasonable, or there is another obvious cause of the AE/SAE. 
Unlikely: 
There is evidence of exposure to the investigational product or there is 
another more likely cause of the AE/SAE. 
Possible: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, but the AE/SAE could have been due to another equally 
likely cause. 
Probable: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, and the AE/SAE is more likely explained by the 
investigational product than by any other cause. 
Definite 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, the AE/SAE is more likely explained by the 
investigational product than by any other cause, and the AE/SAE shows a 
pattern consistent with previous knowledge of the investigational product or 
investigational product class. 


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10.3 
Reporting Plans 
 
The Principal Investigator at BMC/BU Medical Campus will report Unanticipated Problems, 
safety monitors’ reports, and Adverse Events to the BMC/BU Medical Center IRB in accordance 
with IRB policies: 
 Unanticipated Problems occurring at BMC/BU Medical Campus involving a fatal or life-
threatening event will be reported to the IRB within 2 days of the investigator learning of 
the event. 
 Unanticipated Problems occurring at BMC/BU Medical Campus not involving a fatal or 
life-threatening event will be reported to the IRB within 7 days of the investigator learning 
of the event. 
 Reports from safety monitors with recommended changes will be reported to the IRB 
within 7 days of the investigator receiving the report.  
 Adverse Events (including Serious Adverse Events) will be reported in summary at the 
time of continuing review, along with a statement that the pattern of adverse events, in 
total, does not suggest that the research places subjects or others at a greater risk of harm 
than was previously known. 
 Reports from safety monitors with no recommended changes will be reported to the IRB at 
the time of continuing review.  
 
10.4 
Stopping Rules 
 
There are no interim analyses planned that would allow for a determination of futility or 
overwhelming benefit.  Study enrollment will be suspended under the following circumstances: 
 
1.  Serious Adverse Events.  Study enrollment will be suspended in the event of a single serious 
adverse event that is determined to be unexpected and at least possibly related.  If suspended, 
study recruitment will not continue until a determination has been made about whether the 
known risks of participation have changed and the BU Medical Campus/Boston Medical 
Center IRB has made a finding that the risk/benefit ratio remains favorable given the possible 
newly identified risk.   
 
2.  Risk of intoxication.  Subject recruitment will also be suspended if more than one subject of 
the first ten subjects enrolled is discontinued by the investigator due to intoxication during the 
alcohol self administration trial.  Due to differences in alcohol tolerance, BAL is not a reliable 
measure of subjects potentially posing a safety risk.  Medical staff will make a subjective 
determination of risk based on the subject’s behavior.  After 10 subjects have been enrolled, the 
trial will be suspended if there are more than 10% of subjects whose participation has been 
halted by the study team due to concerns about physical safety because of intoxication during the 
alcohol self-administration trial. If suspended for this reason, the study team will consider design 
changes to reduce the likelihood of this as a potential risk to study subjects.  Recruitment would 


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resume when the BU Medical Campus/Boston Medical Center IRB has made a determination 
that proposed changes to the study design have an acceptable risk/benefit ratio. 
 
11 Data Handling and Record Keeping 
 
11.1 
Confidentiality 
 
All staff will be fully trained in the procedures for protection confidential health information.  To 
maintain subject confidentiality, study data will be coded on CRFs that are identified by a subject 
number only. Source records with identifying information and CRFs will be stored in double-
locked space with access only by authorized staff.  Data stored in the REDcap system have 
strong protections including file encryption and password access.  Subject information will not 
be released without written permission.  Upon approval of the study by an IRB, an application 
will be filed with NIAAA for a Certificate of Confidentiality.  
 
11.2 
Source Documents 
 
Source documents in this study include: 
Laboratory test results 
Photocopies of the urine drug screening test result 
ECG tracings 
Subject locator form 
Subject contact form 
 
Data generated by the methods described in the protocol will be recorded in the subjects' source 
binder. Data may be transcribed legibly on CRFs for each subject or directly inputted into an 
electronic system or any combination thereof. 
 
11.3 
Case Report Forms 
 
The study case report form (CRF) will be the primary data collection instrument for the study. 
All data requested on the CRF will be recorded. All missing data will be explained. If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, a 
written explanation will be included to detail why the data was not recorded.  If the item is not 
applicable to the individual case, a notation will be made.  All entries on will be printed legibly 
in black ink. If any entry error has been made, to correct such an error, a single straight line will 
be drawn through the incorrect entry and the correct data will be entered closely to the original 
data. All such changes will be initialed and dated.  There will be no erasures or white-out on 
CRFs.  For clarification of illegible or uncertain entries, the clarification will be printed near the 
item, then initialed and dated. Electronic CRFs in the REDcap system will include an audit trail.   
 
The CRFs that will be used in this study are: 
Demographics 
Concomitant Medications 


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Adverse Events 
Birth Control Assessment 
Urine Drug Screening  
Vital Signs 
Blood Alcohol Level 
Time-line Follow-back 
Pregnancy test 
Birth control assessment 
Medical History 
Physical Examination 
MINI diagnoses summary 
Medication Compliance log 
Eligibility 
ECG 
C-SSRS 
CIWA-AR 
OCDS 
AUQ 
VAS 
COWAT 
Digit Span 
 
11.4 
Study Records Retention 
Study records will be retained for at least seven years after completion of the study.  


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12 Statistical Plan 
 
12.1 
Study Hypotheses and Planned Analyses 
 
For our primary outcomes, separate analyses will be conducted on data collected during the Priming and 
Self-Administration periods of the test session.  
Hypothesis 
Planned Analyses 
1. Subjects will consume 
less alcohol during an 
alcohol self-administration 
trial when receiving 
lacosamide compared to 
when they are receiving 
placebo.     
The volume of alcohol consumed during alcohol challenge trials 1 and 
2 will be used to test the effect of lacosamide on alcohol consumption.  
We will use a mixed models repeated measures approach to test for 
differences between alcohol consumed between the lacosamide and 
placebo self-administration trials61-62.  This data will be divided into 
first and second-hour blocks of self-administration. Within-subject 
factors for this analysis will include treatment and Time Block. Trial 
order will be used as covariate in these analyses to allow evaluation as 
to whether the order of treatments had a significant effect on the 
outcome. Appropriate covariance structures will be determined using 
Akaike’s information criteria to evaluate the best model fit. Results 
analysis will be examined for both treatment effects and the Treatment 
x Time Block interaction results. 
2.  Subjects will report lower 
levels of craving as 
measured by the Visual 
Analog Scale (VAS) and the 
Alcohol Urge questionnaire 
(AUQ) during the 
lacosamide self-
administration trial 
compared to the placebo 
self-administration trial.   
Craving measures (AUQ and VAS) collected at 30-minute intervals 
during the self-administration trials will be used to test the effect of 
lacosamide on alcohol craving.  A mixed models approach will be used 
to test for differences in craving between the lacosamide and placebo 
self-administration trials. Within-subject factors for this analysis will 
include Treatment and Time Block. Trial order will be used as 
covariate in these analyses to allow evaluation as to whether the order 
of treatments has a significant effect on the outcome. 
3. There will be no 
significant difference in 
verbal fluency or working 
memory between trials of 
lacosamide and placebo.    
COWAT and Digit Span scores collected on the day of each self-
administration trial (prior to consumption) will be used to determine the 
effect of lacosamide on verbal fluency and working memory.  A mixed 
model repeated measures approach will be used to test for differences 
in COWAT and digit span scores between the lacosamide trial and the 
placebo trial.   Day and Treatment will be treated as within-subject 
factors.   
4.  Subjects will report lower 
levels of craving and 
consumption during 
lacosamide administration as 
compared to placebo 
administration.      
The alcohol VAS and the TLFB measurements during the seven-day 
period of medication titration will be used to determine the effect of 
lacosamide on craving and consumption.   Mixed Models repeated 
measures approach will be used to test for differences in craving and 
consumption between the lacosamide and placebo trials.  Treatment 
will be used as within-subject factor. VAS measures taken on each of 
the seven days of medication titration, repeated measures mixed models 
analysis will be conducted with Day and Treatment as within-subject 
factors.   
 
12.2 
Sample Size Determination 


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In our initial proposal a group size of 20 completers was selected for use in this study based on 
an assumed effect size of 1.00 suggested by similar alcohol self-administration studies with 
amount consumed as the primary outcome38,63.  This effect size is in the range we found for the 
anticonvulsant drug zonisamide used in an alcohol self-administration study37.  For an estimated 
reduction of 2.1 drinks with an estimated standard deviation (1.48) of the period differences for 
each participant with each sequence, effect size of this magnitude (1.00) requires a sample size 
of 20 that would allow for detection of a significant within-subject difference in alcohol 
consumption with an alpha value of 0.05 and power value of 0.8.   
 
In response to reviewers’ concerns about the need to detect a smaller than large effect 
size we determined the sample size need to detect a moderate effect size (f = 0.25). Assuming a 
correlation among repeated measures of 0.6 and that the assumption of compound symmetry 
holds, for comparison of total drinks obtained at 2 time points, for a power of 0.8, with an alpha 
value of 0.05, a sample size of 28 subjects would be needed for the detection of a moderate effect 
size. The power using this sample size will be greater than 0.8 if data for 4 time points are 
analyzed.  
 
Given that this a laboratory based experiment we do not plan to conduct any planned 
interim analyses in this study. 
 
13 Ethics/Protection of Human Subjects 
 
This study is to be conducted according to applicable US federal regulations and institutional 
policies (which are based in federal regulations, guidance, and ICH Good Clinical Practice 
guidelines). 
 
This protocol and any amendments will be submitted to the Boston Medical Center and Boston 
University Medical Campus IRB, for formal approval of the study conduct. The decision of the 
IRB concerning the conduct of the study will be made in writing to the investigator. A copy of 
the initial IRB approval letter will be provided to the sponsor before commencement of this 
study.  
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. The consent form will be submitted with the protocol for review and approval by the IRB. 
The consent of a subject, using the IRB-approved consent form, must be obtained before that 
subject is submitted to any study procedure. Consent will be documented as required by the IRB.   
 
14 Literature References 
 
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15.  Appendix A: Schedule of Events 
 
Baseline 
(May be 
split 
over 2 
visits) 
Randomization 
Trial 1 
Dispense 
Trial 2 
Clinic Visit # 
0 
1 
2 
3 
4 
Informed Consent 
X 
 
 
 
 
Urine Drug ScreenA 
X 
X 
X 
X 
X 
Locator Form  
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Physical Exam 
X 
 
 
 
 
MINI V 6.0 
X 
 
 
 
 
Clinical Hematology and Chemistry 
BUN, Ca, CO2, Cl, Cr, G K, Na, 
Triglycerides, AST, ALT, GGT, 
Tbili 
X 
 
 
 
 
Urinalysis 
X 
 
 
 
 
COWAT, Digit Span, Spatial Span 
 
 
X 
 
X 
Vital Signs, weight, Blood Alcohol 
Levelb 
XX 
X 
X 
X 
X 
ECG 
X 
 
 
 
 
Prior and Concomitant Meds 
X 
X 
X 
X 
X 
CIWA-AR 
X 
X 
X 
X 
X 
Eligibility Checklist 
X 
 
 
 
 
Drug compliance/accountability 
 
 
X 
 
X 
Urine Pregnancy Test   
X 
X 
X 
X 
X 
Birth control assessment 
X 
X 
X 
X 
 
AEs 
X 
X 
X 
X 
X 
C-SSRS 
X 
X 
X 
X 
X 
Dispense medication/placebo 
 
X 
 
X 
 
Brief Telephone Interview 
 
Mid-week call 
 3-4 days after 
starting 
medication 
 
Mid-week call 
3-4 days after 
starting 
medication 
 
Treatment Referral 
 
 
 
 
X 
TLFB (28 day at baseline) 
X 
X 
X 
X 
X 
VAS 
 
X 
X 
X 
X 
OCDS 
 
X 
X 
X 
X 
AUQ 
 
X 
X 
X 
X 


Lacosamide effects on alcohol self administration and craving in heavy drinkers   
Version 3.12 3.11.19 
Page 33 of 34 
 
A)  Test for opioids, cocaine, amphetamines, methamphetamine, tetrahydrocannabinol (THC), barbiturates, 
oxycodone, buprenorphine, methadone and benzodiazepines.  
B) if the  baseline visit is split between two days, vitals, breathalyzer, and weight are to be taken at each visit.   


Lacosamide effects on alcohol self administration and craving in heavy drinkers   
Version 3.12 3.11.19 
Page 34 of 34 
 
16.  Appendix B: Schedule of assessments during the alcohol challenge 
 
 
 
Observation 
Self-admin 
Block1 
Self-admin 
Block2 
Assessment 
 
 
 
BAC 
Every 10 minutes 
Every 30 minutes 
Every 30 minutes 
VAS
a) 
Every 10 minutes 
Every 30 minutes 
Every 30 minutes 
AUQ  
 
Every 30 minutes 
Every 30 minutes 
 

ICF_001.pdf: