A Double-Blind, Placebo-Controlled Trial Assessing the Efficacy of Levetiracetam Extended
Release in Very Heavy Drinking Alcohol-Dependent Patients
Joanne B. Fertig, Ph.D.1, Megan L. Ryan, B.S., CCRP1, Daniel E. Falk, Ph.D.1, Raye Z.
Litten, Ph.D.1, Margaret E. Mattson, Ph.D.2, Janet Ransom, Ph.D.3, William J.
Rickman, Ph.D.3, Charles Scott, Ph.D.3, Domenic Ciraulo, M.D.4, Alan I. Green, M.D.5,
Nassima Ait-Daoud Tiouririne, M.D.6, Bankole Johnson, M.D., Ph.D.7, Helen Pettinati,
Ph.D.8, Eric C. Strain, M.D.9, Eric Devine, Ph.D.4, Mary F. Brunette, M.D.10, Kyle
Kampman, M.D.8, D. Andrew Tompkins, M.D.9, Robert Stout, Ph.D.11, and the NCIG-
002 Study Group
1Division of Treatment and Recovery Research, National Institute on Alcohol Abuse
and Alcoholism, Bethesda, MD; 2Center for Behavioral Health Statistics and Quality,
Substance Abuse and Mental Health Services Administration (SAMHSA), Rockville,
MD; 3FastTrack Drugs and Biologics, North Potomac, MD; 4Boston University School
of Medicine, Boston, MA; 5Department of Psychiatry, Dartmouth Medical School
(DHMC), Lebanon, NH; 6University of Virginia Center for Addiction Research and
Education, Richmond, VA; 7Center for Addiction Research and Education
Department of Psychiatric Medicine, University of Virginia, Charlottesville, VA;
8Treatment Research Center, Perelman School of Medicine University of
Pennsylvania Treatment Research Center, Philadelphia, PA; 9Johns Hopkins
University School of Medicine, Baltimore, MD; 10Psychopharmacology Research
Group, Department of Psychiatry, Dartmouth Medical School, Concord, NH; and
11Decision Sciences Institute/PIRE, Pawtucket, RI
National Institute on Alcohol Abuse and Alcoholism (NIAAA) Clinical Investigations
Group, Study 2 (NCIG 002)
Boston University School of Medicine, Boston, MA: Ofra Sarid-Segal, M.D.; Maryam
Afshar, M.D.; Chris Streeter, M.D.; Courtney Richambault, B.A.; Matthew Biondolillo,
B.S.; Laurie Sickles-Colanari, R.N.
University of Pennsylvania Treatment Research Center, Philadelphia, PA: Elizabeth
Mahoney, M.A.; Kelly Farraday, B.S.; Gail Kaempf, CRPN; Brenda Beitler, APRN;
Cynthia Clark, CPRN; Margo Hendrickson, MSS, LCSW; Donna Giles; William Dundon,
University of Virginia Center for Addiction Research and Education, Richmond, VA:
Eva Jenkins-Mendoza, B.S., CCRP; Sean Sembrowich, R.N.; Ester Makanjuola, R.N.;
Tricia Schirmer, B.S.
Johns Hopkins University School of Medicine: George E. Bigelow, Ph.D.; Jenna
Cohen M.S.; Delphine Duschel, LPN; Joseph Harrison, B.S.; Kori Kindbom, M.A.;
Jennifer Mucha, M.A.; Leticia Nanda, M.S., CRNP; Kimberly Nelson, LPN; Shirley
Dartmouth Medical School, Lebanon, NH: Audrey Kern, M.D.; Christopher O’Keefe,
M.A.; Shannon Rondeau, R.N., Marjorie Weeks, M.P.A; Joseph Rancourt
FastTrack Drugs and Biologics, North Potomac, MD: Ngami Donovan, B.S.; Marian
Mannion, B.S.; Katrina Kell, B.S., CCRA; Katarina Ujhazy, M.D., CCRP; Hermon
Gebrehiwet, B.S., CCRP and Josh Berman, M.D., Ph.D.
Joanne Fertig, Ph.D.
National Institute on Alcohol and Alcoholism,
National Institutes of Health
5635 Fishers Lane, Room 2041
Rockville, MD, 20852
Phone: (301) 443–0635
Fax: (301) 443–8774
This research was supported by the National Institute on Alcohol Abuse and Alcoholism,
National Institutes of Health, Department of Health and Human Services. Fast Track Drugs and
Biologics was the Coordinating Center.
Background: Despite advances in the development of medications to treat alcohol
dependence, few medications have been approved by the U.S. Food and Drug
Administration. The use of certain anticonvulsant medications has demonstrated
potential efficacy in treating alcohol dependence. Previous research suggests that
the anticonvulsant levetiracetam may be beneficial in an alcohol-dependent
population of very heavy drinkers.
Methods: In this double-blind, randomized, placebo-controlled clinical trial, 130
alcohol-dependent patients who reported very heavy drinking were recruited across
5 clinical sites. Patients received either levetiracetam extended-release (XR) or
placebo and a Brief Behavioral Compliance Enhancement Treatment intervention.
Levetiracetam XR was titrated during the first 4 weeks to 2000 mg/day. This target
dose was maintained during Weeks 5 through 14 and was tapered during Weeks 15
Results: No significant differences were detected between the levetiracetam XR and
placebo groups in either the primary outcomes (percent heavy drinking days and
percent subjects with no heavy drinking days) or in other secondary drinking
outcomes. Treatment groups did not differ on a number of nondrinking outcomes,
including depression, anxiety, mood, and quality of life. The only difference
observed was in alcohol-related consequences. The levetiracetam XR treatment
group showed significantly fewer consequences than did the placebo group during
the maintenance period (p=0.02). Levetiracetam XR was well-tolerated, with fatigue
being the only significantly elevated adverse event, compared with placebo (53% vs.
24%, respectively; p=0.001).
Conclusions: This multisite clinical trial showed no efficacy for levetiracetam XR
compared with placebo in reducing alcohol consumption in heavy drinking alcohol-
Key words: Alcohol Dependence, Levetiracetam, Keppra®, Medications
Development, Alcohol Use Disorder
Alcohol use disorders (AUDs) (alcohol dependence and abuse) are heterogeneous
disorders that affect 18 million Americans (Grant et al., 2004), causing a wide range of medical,
psychological, social, personal, and economic problems. Up to 40 percent of patients who are
hospitalized have AUDs (de Wit et al., 2010). The total economic cost of alcohol use in the
United States is estimated to be $235 billion annually (Rehm et al., 2009). Encouragingly,
advances have been made in treatment approaches, especially in the development of
medications specifically targeting alcohol drinking.
Currently, three medications (four formulations) are approved by the U.S. Food and
Drug Administration (FDA) for the treatment of alcohol dependence: disulfiram (Antabuse® or
Antabus®), oral naltrexone (Revia® or Depade®), acamprosate (Campral®), and injectable
naltrexone (Vivitrol®) (Johnson, 2008; Litten et al., 2005). While these medications have
demonstrated small to moderate effect sizes in clinical trials, the search for new molecular
targets and more efficacious drug compounds are under way in a number of clinical trials
Several randomized, placebo-controlled trials (RCTs) suggest that anticonvulsant
medications may reduce drinking among people with alcohol dependence (De Sousa, 2010;
Book and Myrick, 2005). The most encouraging results, so far, have been with topiramate.
Johnson et al. (2007) demonstrated, in a multi-site trial, efficacy for topiramate over placebo in
reducing drinking in alcohol dependent patients—an effect greater than that observed with
other alcohol medications in multi-site trials (Johnson, 2008; Litten et al., 2005). Gabapentin
and zonisamide also have been tested and demonstrated some efficacy. Anton et al. (2009)
reported that alcohol dependent patients who experienced pre-treatment withdrawal
symptoms had fewer drinking days when treated with gabapentin in combination with
flumazenil compared with placebo-treated patients. In addition, Anton et al. (2011)
demonstrated that adding gabapentin to naltrexone for the treatment of patients with alcohol
dependence resulted in fewer heavy drinking days than treatment with naltrexone alone. In a
preliminary study, Arias et al. (2010) found that alcohol dependent patients treated with
zonisamide had fewer heavy drinking days and consumed less drinks per week, compared with
Levetiracetam is another anticonvulsant medication that has shown promise for the
treatment of alcohol dependence. Its mechanism of action is somewhat different from other
antiepileptic medications. Levetiracetam activates the γ-aminobutyric acid (GABA) and glycine
systems, interacts with the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) receptors, and partially depresses the N calcium current (Abou-Khalil, 2008; Carunchio
et al., 2007; De Smedt et al., 2007a; Sanchis-Segura et al., 2006; Rigo et al., 2002)—all targets
that have been associated with alcohol-seeking and drinking behavior (Litten et al., 2005). In
addition, levetiracetam modulates the synaptic vesicle protein 2A (SV2A), an action that
appears to correlate with seizure protection (Abou-Khalil, 2008; Kaminski et al., 2008; De Smedt
et al., 2007a). The metabolism of levetiracetam is minimal; its elimination occurs almost
completely through the urinary system (De Smedt et al., 2007b). Moreover, levetiracetam is
well-tolerated, with fewer side-effects than observed with other anticonvulsants (Abou-Khalil,
2008; De Smedt et al., 2007b). Although supratherapeutic doses of levetiracetam (4000 mg)
have met criteria for demonstrating abuse potential in the laboratory, levetiracetam has not
been associated with reports of actual abuse in the marketplace (Feltner & Haig, 2011).
Levetiracetam appears promising as a medication for reducing or preventing harmful
drinking. In animal models, levetiracetam reduced voluntary alcohol intake in alcohol preferring
rats (Zalewska-Kaszubska et al., 2011). Although levetiracetam has been shown to be effective
in treating alcohol withdrawal symptoms in several open label trials (Muller et al., 2010; Krebs
et al., 2006), a recent multi-site trial failed to show an advantage over placebo, and diazepam
was required as a rescue medication (Richter et al., 2010). Nonetheless, two recent open label
studies have indicated the clinical efficacy of levetiracetam. Sarid-Segal et al. (2008) reported a
significant decline in drinks per day, alcohol craving, and alcohol severity over 10 weeks of
treatment with up to 2000 mg levetiracetam in 20 alcohol dependent patients. Mariani and
Levin (2008) reported reduced alcohol consumption (i.e., drinking days/week, percent heavy
drinking days, and percent days abstinent) and anxiety symptoms after 8 weeks of treatment
with levetiracetam (up to 1500 mg twice daily) in a case series of three patients with comorbid
alcohol dependence and an anxiety disorder. In addition, levetiracetam was well-tolerated in
alcohol dependent patients in both studies.
In summary, preliminary results suggest that levetiracetam may be beneficial as a
treatment for alcohol dependence. The purpose of this study was to assess both the efficacy
and safety of levetiracetam XR (extended-release) in very heavy drinking alcohol dependent
patients. A 4-month, randomized, multi-site, placebo-controlled, double-blind clinical trial was
conducted assessing levetiracetam XR’s effect on drinking outcomes, alcohol-related
consequences, quality of life, mood, anxiety, depression, and safety. The trial was registered in
ClinicalTrials.gov (Identifier: NCT00970814).
Randomized patients (n=130) included 99 men and 31 women who were diagnosed with
alcohol dependence (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
[DSM–IV]; American Psychiatric Association, 1994). Interested candidates responded by
telephone to advertisements at 5 academic sites in the United States between November 2009
and May 2010. During the initial telephone call screen, a brief set of standardized questions
about drinking were asked to preliminarily determine whether study drinking criteria could be
met and to ascertain the caller’s interest in study participation. Individuals who reported levels
of drinking consistent with the study entry criteria were scheduled for an in-person screening
visit. Interested patients who were able to provide a breath alcohol concentration (BAC) equal
to 0.00 at a consent meeting then received information on the study and signed an informed
consent form (approved by each clinical site’s Institutional Review Board1) before beginning any
study assessments. Additionally, patients provided detailed baseline drinking histories and were
given health screens and psychosocial assessments.
1 Each clinical site also obtained a Certificate of Confidentiality issued by NIAAA.
Key inclusion criteria included: 1) alcohol dependence, determined by DSM–IV criteria;
2) age 18 or older; and 3) drinking very heavily (10 or more drinks/drinking day for men; 8 or
more drinks/drinking day for women) at least 40% of the days during any consecutive 60-day
interval during the 90-day period before the clinic screening visit, with at least 1 heavy drinking
day (5 or more drinks/drinking day for men; 4 or more drinks/day for women) occurring within
the 14 days before randomization (a standard drink was 0.5 oz of absolute alcohol, equivalent
to 10 oz of beer, 4 oz of wine, or 1 oz of 100-proof liquor) (Miller et al., 1991).
Key exclusion criteria included: 1) past-year DSM–IV dependence on any psychoactive
substances other than alcohol and nicotine; 2) other psychiatric illnesses, including a lifetime
DSM–IV diagnosis of panic disorder with or without agoraphobia, schizophrenia, bipolar
disorder, or other psychosis; past-year diagnosis of major depression, or past-3-month
diagnosis of an eating disorder; 3) inability to be safely withdrawn from alcohol on an
outpatient basis (e.g., CIWA–AR score>10) or having undergone medical detoxification during
the screening phase; 4) pharmacotherapy for alcohol dependence within 1 month before
randomization; 5) current psychotherapy for alcohol problems; 6) abnormal calculated
creatinine clearance defined as < 80 mL/min; 7) non-stable use of a Selective Serotonin
Reuptake Inhibitor (SSRI) (defined as taking an SSRI for less than 3 months prior to informed
consent); 8) current use of a dual uptake inhibitor, serotonin-norepinephrine reuptake inhibitor
(SNRI), tricyclic antidepressant, or monoamine oxidase inhibitor (MAOIs) antidepressant; and 9)
use of anticonvulsants, hypnotics, antipsychotics, psychomotor stimulants, or anti-anxiety
agents in the 14 days prior to randomization.
In-clinic assessments were carried out at screening, baseline, and at the beginning of
Weeks 2, 3, 4, 6, 8, 10, 12, 14, 15, and 17, whereas brief telephone assessments were
conducted at the beginning of Weeks 5, 7, 9, 11, 13, and 16 (Table 1). A follow-up telephone
interview to assess safety and changes in drinking was performed at Week 19, approximately 2
weeks after the last in-clinic study visit. Patients were not allowed to complete in-clinic
assessments unless they had a BAC < 0.02%.
This study was conducted in accordance with good clinical practices (International
Conference on Harmonisation, 1996). Patients who met eligibility criteria at the end of the
screening visit were randomly assigned, within 14 days and in an approximate 1:1 ratio, to
receive either levetiracetam XR or placebo using a permuted stratified block randomization
procedure with clinical site (subsites were considered separate clinical sites) and SSRI use as
stratification variables. SSRI use was defined as taking a stable regimen of SSRIs for the 3-month
period prior to signing the informed consent with plans to continue the same SSRI regimen
during the study. SSRI users were limited to no more than 30% of the target enrollment at each
site. Stable SSRI use was acceptable for the study because many alcohol dependent women
take SSRIs; and, thus, disallowing SSRI use could have negatively impacted the ability of the
study to enroll female patients. Consequently, SSRI use was then treated as a stratification
variable to control for its potentially confounding effect on study outcomes. Randomization was
implemented via a voice- or Web-based randomization system.
Double-blind study medication was dispensed to patients for 16 weeks. Levetiracetam
XR (Keppra XR®) was supplied in 500 mg over-encapsulated (OE) tablets with identical matching
placebos. During the first 4 weeks after randomization, the dose was titrated from a starting
dose of 500 mg/day up to a target dose of 2000 mg/day. This target dose was maintained
during Weeks 5 through 14. A dose taper occurred during Weeks 15 and 16 during which the
dose was reduced by half each week. Patients assigned to the placebo group received matched
placebo and followed the same dosing schedule as the levetiracetam XR group. Patients unable
to tolerate the 2000 mg/day target dose were allowed to continue in the study at a lower dose.
Patients who discontinued medication during the study were allowed to remain in the study
and participate in study assessments. Medication compliance was determined by corroborating
the patient’s self-reported daily dose taken with the number of pills removed from the weekly
blister pack, which was returned by the patient at each clinic visit.
All patients received Brief Behavioral Compliance Enhancement Treatment (BBCET)
(Johnson et al., 2007). BBCET is a brief (15 to 30 minutes per session) standardized treatment
platform used in conjunction with a pharmacological intervention for the treatment of alcohol
dependence. The purpose of BBCET is to enhance compliance with the medication and with
other aspects of the treatment regimen. BBCET sessions address patient issues relating to
personal barriers of compliance, focusing on how medication can assist the patient in achieving
his or her own goals related to the control of drinking, and, if necessary, addressing the
management of adverse events. The first session was delivered at the randomization visit, with
subsequent sessions occurring at each in-person clinic visit thereafter for a total of 11 sessions.
BBCET administrators were certified and monitored for compliance with the BBCET guidelines
throughout the study.
Analytic Plan and Statistical Methods
The primary efficacy outcomes were weekly percent days heavy drinking (HDDs) and
percent of subjects with no heavy drinking days (PSNHDDs) during study Weeks 5–14. A grace
period of the first 4 weeks was permitted to titrate levetiracetam XR to the selected
therapeutic dose, whereas Weeks 15 and 16 were allowed for dose tapering. Secondary
outcome measures included other drinking measures (drinks per day, drinks per drinking day,
percent days abstinent, percent very heavy drinking days [10+/8+], and percent subjects
abstinent) that also were assessed during Weeks 5–14, as well as alcohol-related consequences,
depression, anxiety, mood, and quality of life. Skewed variables were transformed as follows:
log transformations (percent very heavy drinking days, Montgomery-Asberg Depression Scale
[MADRS], and Hamilton Anxiety Rating Scale [HAM-A]) and square root transformations (drinks
per day, drinks per drinking day, Drinker Inventory of Consequences [DrInC], and Profile of
Mood States [POMS]).
All outcome measures were analyzed for an intention-to-treat (ITT) population that
included all randomized patients (n=130). Continuous outcomes were analyzed using a
repeated-measures mixed effects model with patients treated as the random effect. A Toeplitz
covariance matrix best fit the data and was used to model the correlations between repeated
measures among patients. For descriptive purposes, least-square means (LSMEANs), standard
errors (SEs), and 95% confidence intervals (CIs) are presented for each treatment group and
were derived from unadjusted models with untransformed outcome variables and two
predictors: week and treatment group. Corresponding Cohen’s d and p-values were derived
from adjusted models with appropriately transformed outcome variables and included the
covariates age, clinical site, SSRI use, and baseline value of the outcome. For continuous
outcomes assessed at a single time (e.g., SF-12 and POMS), unadjusted means are presented
for untransformed variables. Cohen’s d and p-values were derived from general linear models
(ANCOVAs) with appropriately transformed outcome variables and included the same covariate
scheme as the repeated-measures models. Single dichotomous drinking outcomes (i.e.,
abstinence and no heavy drinking) were computed to reflect drinking across the entire
maintenance period (Weeks 5–14). Prevalence rates are presented for untransformed
variables. Odds ratios (ORs) and p-values were derived from logistic regression models, again
with the same covariate scheme. However, because there was no variability in the baseline
equivalents of these outcome variables, percent days abstinent was used as the covariate for
the abstinence outcome, and percent heavy drinking days was used as the covariate for the no
heavy drinking outcome. All baseline drinking measures were computed during a 60-day period
(Days 31–90 before the first screening visit). Outcomes for laboratory tests, safety measures,
and vital signs were analyzed via paired t-tests that compared treatment group differences on
change scores from baseline to Week 15 and by examining the frequencies of patients that
shifted from a normal status at baseline to a clinically significant abnormal status at the end of
treatment. To determine the effect of missing drinking data during treatment, models for the
primary outcomes were rerun with missing drinking data imputed as heavy drinking days.
All analyses were re-run on an evaluable subsample in order to determine whether the
treatment effect was improved among high compliance patients. The evaluable subsample was
defined as those patients who took at least 500 mg (the minimal study dose) on at least 80% of
study days during the maintenance period of the trial (i.e., on at least 56 of the 70 days during
Study Weeks 5–14). Of the 130 randomized subjects, 95 (73.1%) were included in the evaluable
A series of additional exploratory subgroup analyses were conducted to determine if a
differential treatment effect existed as a function of subgroup status for the primary outcome,
percent heavy drinking days, during the maintenance period. Subgroups included gender, age
of onset of regular drinking (early onset < age 18; later onset > age 18), years of exposure to
drinking (i.e., age – age of onset of regular drinking; dichotomized at the median = 27 years),
and baseline MADRS (normal <7; depressed > 7), and marijuana use based on a positive urine
drug screen. For all subgroups except marijuana use, LSMEANS, 95% CIs, and p-values for
treatment by subgroup interactions and simple effects were tested for significance via mixed
effects models that included week, treatment group, subgroup, and treatment by subgroup
interaction (adjusted for age, clinical site, SSRI use, and baseline percent heavy drinking days).
Due to the small number of patients testing positive for marijuana use, a fully adjusted
subsample analysis was run for the primary outcome variable on marijuana-negative patients
For bivariate comparisons, treatment group differences were tested for significance by
t-tests for independent samples (for normally distributed variables) or Wilcoxon rank-sum tests
(for skewed variables); prevalence rate differences were tested for significance via chi-square or
Fisher’s exact tests. For all statistical tests, p<0.05 (two-tailed) was considered statistically
significant. For the primary outcome, percent heavy drinking days, it was estimated that a
sample size of 130 patients was required to obtain 104 evaluable patients (52 per treatment
group), yielding 80% power to detect a treatment effect (Cohen’s d=0.66) with a two-tailed t-
test at a .05 significance level. For the other primary outcome, percent subjects with no heavy
drinking days, 80% power would be achieved given a placebo response rate of 30% and a
medication response rate of 62%. Data were analyzed with SAS version 9.2 (SAS Institute, Inc.,
A total of 295 patients consented for the study, 130 of which were randomized and 165
were excluded for either not meeting eligibility criteria or choosing not to participate. The main
reason for screen failures included not meeting drinking criteria (25.5%), positive urine
toxicology drug screen (17.6%) and not completing screening (10.3%). Of the 130 randomized
patients, 66 were randomized to placebo and 64 were randomized to levetiracetam XR. One
patient randomized to the placebo group dropped out of the study prior to receiving study
medication. Except for a difference in age (placebo 47.0 years, levetiracetam XR 41.7 years;
p=0.011) and POMS score (placebo 63.5, levetiracetam 54.6; p<0.0001)2, patients in the
levetiracetam XR and placebo groups had statistically similar values on all baseline
characteristics (Table 2). Randomized patients were mostly male, white, employed, and middle
aged. On average, they drank very heavily—meeting or exceeding a 10/8 drinks per drinking
day threshold for men and women, respectively, on approximately 75% of days. This rate of
very heavy drinking translated to average consumption of about 16 drinks per drinking day.
Despite high levels of heavy drinking, most patients had no or very mild depressive symptoms
at baseline (64.3% were non-depressed [MADRS <7]; 28.7% had mild depression [MADRS = 7–
19]; 7.0% had moderate depression [MADRS = 20–34]) (Montgomery and Asberg, 1979). In
addition, very few patients displayed significant anxiety (96.9% were normal [HAM-A < 14];
3.1% had at least mild anxiety [HAM-A > 14]) (Guy, 1976). Also, at baseline, subjects had slightly
above-normal physical functioning (SF12 physical aggregate score = 52.1) and slightly below-
normal mental functioning (SF12 mental aggregate score = 47.2).
Medication Compliance/Complete Drinking Data
Overall compliance with study medication, defined as the proportion of total prescribed
medication taken during the maintenance phase of the study (Weeks 5–14), was 94.5% and was
similar between the treatment groups (95.0% for the placebo group vs. 94.0% for the
levetiracetam XR group; p=0.66). The average daily dose of medication taken was 1820 mg (or
3.64 of the 4 possible pills) in the placebo group and 1755 mg (or 3.51 of the 4 possible pills) in
2 Baseline POMS was not chosen as a covariate in mixed models because of its very low correlation with drinking
and non-drinking (non-POMS) outcomes.
the levetiracetam XR group (p= 0.652). Research participation rate, defined as percent of
patients with complete drinking data during the maintenance phase (Weeks 5–14), was 81.5%
overall and was slightly higher in the placebo group than the levetiracetam XR group (84.8% vs.
78.1%, respectively), though this difference was not statistically significant (p=0.323). Overall,
37 patients (28.5%) discontinued the study drug prior to completing the study, with a larger
proportion of patients discontinuing in the levetiracetam XR group compared with the placebo
group (35.9% vs. 21.2%, respectively; p=0.063). Most discontinuation was the result of patients
dropping out of the study (23 patients), but also included 14 patients who discontinued the
study drug yet remained in the study for followup.
Two primary efficacy outcome measures, percent heavy drinking days (HDDs) and
percent subjects with no heavy drinking days (PSNHDDs) were defined a priori. Regarding
percent HDDs, the levetiracetam XR and placebo groups had statistically similar weekly
unadjusted treatment group means during all weeks of the study (all p>0.14) and particularly
during the study maintenance phase (Weeks 5–14) (all p>.19) (Figure 1). Fully adjusted models
further failed to show significant differences between the treatment groups on this outcome
(p=0.58), PSNHDDs (p=0.95), as well as five secondary drinking outcomes during Weeks 5–14,
including percent days abstinent (p=0.92), drinks per day (p=0.84), drinks per drinking day
(p=0.83), percent very heavy drinking days (p=0.80), and percent subjects abstinent (p=1.00)
(Table 3). Similar results for the primary outcomes were obtained when missing drinking data
were imputed as heavy drinking days (percent HDDs, p=0.93; PSNHDDs, p=0.95).
Treatment groups also did not differ significantly during the maintenance period on a
number of nondrinking measures, including quality-of-life mental scale (SF-12) (p=0.54), anxiety
(HAM-A) (p=0.31), depression (MADRS) (p=0.59) and mood (POMS) (p=0.60) (Table 3).
Furthermore, smoking behaviors did not change during the study or between groups.
In contrast, the levetiracetam XR group had significantly lower alcohol-related
consequences (DrInC total score) as compared with placebo during the treatment maintenance
period (p=0.02). When the subscales of the DrInC were evaluated, the impulsive (p=0.03),
physical (p=0.01), and intrapersonal (p=0.01) subscale scores were significantly lower in the
levetiracetam XR group than the placebo group, whereas the interpersonal (p=0.13) and social
(p=0.23) subscales scores did not differ significantly between the two groups (data not shown).
Finally, the levetiracetam XR group displayed a trend (p=0.08) toward a lower quality of life on
the SF-12 physical subscale score compared with the placebo group.
Across all outcomes, model results obtained with the high-compliance, evaluable
subsample were similar to those results obtained with general ITT population. For example,
treatment effects for both primary outcomes remained non-significant within the evaluable
subsample (percent HDDs, p=0.37; PSNHDDs, p=0.45). A number of other analyses were
performed to identify subgroups that might have responded to levetiracetam XR using the
outcome percent heavy drinking days. Mixed model results revealed no significant differential
treatment effects as a function of gender (interaction p=0.41), age of onset of regular drinking
(p=0.80), years exposure to drinking (p=0.45), and depression (MADRS) score (p=0.78). There
were also no differential treatment effects in the marijuana-negative drug screen subsample
Safety and Adverse Events
Changes in mood, alcohol withdrawal (CIWA-AR> 10), vital signs, weight,
electrocardiogram (ECG), and clinical laboratory results were unremarkable during the study
and generally were similar between the treatment groups. Although GGT decreased in both
groups, the decrease was greater in patients taking placebo than levetiracetam XR (-21 U/L vs. -
14 U/L, respectively; p<.04); yet no patients from either group experienced a clinically
significant shift from baseline in GGT values.
Of the 1029 adverse events reported (in 121 patients) during the treatment phase of the
study, 56.9% of those events were mild, 38.3% were moderate, and 4.2% were severe, with
statistically equal proportions within each category occurring among the levetiracetam XR and
placebo groups. Treatment emergent adverse events occurring in at least 10% of patients
included (from most to least frequent): fatigue, headache, insomnia, nausea, irritability,
depressed mood, anxiety, arthralgia, somnolence, dizziness, paraesthesia, upper respiratory
tract infection, vomiting, back pain, diarrhea, and pruritus (Table 4). Of these adverse events,
fatigue was the only one that differed significantly by treatment group, with the prevalence
rate in the levetiracetam XR group being more than two times that of the placebo group (53.1%
vs. 24.2%, respectively; p=0.001).
Thirteen unique serious adverse events occurred during the maintenance phase of the
trial, 3 in the levetiracetam XR group and 10 in the placebo group. Of the 3 in the levetiracetam
XR group (inpatient alcohol detoxification, abortion of pregnancy, and thought of self-harm),
none were considered related to the investigational product.
There are compelling reasons to conduct an early proof-of-concept clinical trial of
levetiracetam for the treatment of alcohol-dependent patients. First, a number of other
anticonvulsants, including topiramate, gabapentin, zonisamide, valproic acid, and
carbamazepine, have shown promise in reducing drinking and acute alcohol withdrawal
symptoms (Arias et al., 2010; De Sousa, 2010; Book and Myrick, 2005; Litten et al., 2005).
Second, levetiracetam binds to several targets, including GABA, glycine, and N calcium
channels, all of which have been shown to alter alcohol-seeking and drinking behavior (Perkins
et al., 2010; Litten et al., 2005). Moreover, levetiracetam binds uniquely to SV2A, which
recently has been correlated with the prevention of seizures and may be related to the
reduction of alcohol consumption (Abou-Khalil, 2008; Kaminski et al, 2008). Third, two open
label clinical trials have shown efficacy of levetiracetam in treating alcohol dependent patients
(Sarid-Segal et al., 2008; Mariani and Levin, 2008). Finally, levetiracetam is well tolerated and
has an attractive safety profile for an anticonvulsant. Levetiracetam has no cognitive side
effects, an improvement over other anticonvulsants, including topiramate (Gomer et al., 2007).
In this multi-site controlled clinical trial, levetiracetam XR failed to demonstrate efficacy
in reducing alcohol consumption in very heavy drinking alcohol dependent patients. There was
no effect on the primary outcome measures of percent HDDs and PSNHDDs (Table 3).
Moreover, there were no differences between levetiracetam XR and placebo groups in
secondary drinking and non-drinking outcome measures (Table 3). In addition, there were no
differences in non-drinking outcomes of depression, anxiety, and quality of life. Only the
alcohol-related consequences, as measured using the DrInC questionnaire, showed a significant
difference between the levetiracetam XR and placebo groups (with the former experiencing
fewer consequences than the latter). However, this result is difficult to explain given the
negative findings for alcohol consumption, especially because DrInC scores have been shown to
correlate with drinking (Falk et al., 2010). Perhaps the greater fatigue associated with
levetiracetam XR may mediate the relationship between treatment group and DrInC scores.
For example, patients with greater fatigue may have less impulsive behavior associated with
drinking. Alternatively, correction for multiple statistical tests was not used in this study;
therefore, the significant DrInC result may be spurious.
A number of subgroup analyses further failed to demonstrate significant efficacy for
levetiracetam XR above placebo. For instance, model results obtained from an evaluable
subsample were similar to those obtained in the overall ITT population, suggesting that
levetiracetam XR was no more efficacious than placebo even among patients with high
compliance to the medication regimen. The treatment effect also remained non-significant in a
subsample of patients who screened negative for marijuana at baseline. Likewise, the
treatment effect did not significantly vary as a function of gender, age of onset of regular
drinking, years of exposure to drinking, or baseline depression.
It is possible that the target dosage of levetiracetam XR in this study was not the
therapeutic dose, explaining its lack of efficacy. Our target dose of 2000 mg daily is the dosage
commonly used to treat seizures (De Smedt et al., 2007b; Abou-Khalil, 2008). Doses of 3000 mg
and 4000 mg daily have also been used to treat seizures, although the number of adverse
events, particularly irritability, appears to increase when doses of 3000 mg are used with
alcohol dependent patients (D. Ciraulo, personal communication).
Medications for the treatment of AUDs are not uniformly and broadly effective; it
appears that particular medications work for only particular patients or subgroups. We
conducted a number of preliminary analyses for various subtypes to see if levetiracetam XR’s
possible efficacy could be matched to a certain group of patients. We examined groups defined
by gender, age of onset of regular drinking, years of exposure to drinking, DrInC scores (total
and impulsivity subscales), anxiety, and depression. None of the subgroup analyses, however,
revealed any differential treatment effect between the levetiracetam XR and placebo groups.
Levetiracetam XR was well tolerated by the alcohol dependent patients. Fatigue was the
only side-effect that was significantly elevated in the levetiracetam XR group compared with
placebo. In contrast, in a recent multi-site trial, the side-effect profile of topiramate yielded at
least five side-effects that were significantly more frequent in alcoholic patients administered
topiramate than in those who were taking placebo (Johnson et al., 2007). Perhaps, at least with
anticonvulsants, the presence of side-effects is related to efficacy. Side effects may indicate the
potency of the medication; or possibly, the side-effects are part of the mechanism that causes a
person to reduce his or her drinking.
Because of the heterogeneity and complexity of AUDs, there is currently not one
medication for the treatment of alcoholism that is effective and acceptable for all patients.
Research is ongoing to develop more efficacious and safe medications to treat AUDs. It is
important to make further progress in understanding the mechanisms underlying alcohol-
seeking and drinking behavior, and it is hoped that this will lead to the discovery of new, more
effective molecular targets for drug development. In this study, we recruited a subpopulation of
very heavy drinkers who were functional, who did not require detoxification, and who were
without signs of active and significant depression and anxiety. It is possible that other
subpopulations might have positively responded to this compound. However, the present
results do not support the use of levetiracetam XR at a dose of 2000 mg per day as a treatment
for alcohol dependence.
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Table 1. Assessment Schedule
Assessment & Source
Breath alcohol concentration (BAC)
Brief Drinking Assessment
Clinical Institute Withdrawal Assessment for Alcohol - Revised (CIWR–AR) (Sullivan et al., 1989) Each Contact
Drinker Inventory of Consequences (DrInC) (Miller, 1995)
Fagerström Test for Nicotine Dependence (Heatherton et al., 1991)
Hamilton Anxiety Scale (HAM-A) (Guy, 1976)
Montgomery-Asberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979)
Motivation to Reduce Drinking
Profile of Moods Questionnaire (POMS)
Prior medications (past 30 days)
Quality of Life Short Form 12 (SF-12) (Szabo, 1996)
Time-Line Follow-Back (Sobell and Sobell, 1992)c
Urine drug screen
Urine pregnancy test
Vital signs (blood pressure, heart rate, and respiration rate) and weight
a All assessments were conducted in the clinic, except for weeks 5, 7, 9, 11, 13, 16, 19 which were conducted via telephone.
b Blood chemistries were assessed after >2 hours of fasting; repeated after >8 hours if blood glucose or triglycerides were elevated.
SCR, BL, 2, 3, 4, 6, 8, 10, 12, 14, 15, 17
SCR, 4, 15
BL, 4, 8, 12, 15, 17
BL, 8, 15
BL, 4, 8, 12, 15, 17
SCR, 4, 15
SCR, BL, 4, 8, 12, 15, 17
BL, 2, 3, 4, 12, 17
BL, 8, 17
SCR, BL, 2, 3, 4, 6, 8, 10, 12, 14, 15, 17
2, 3, 4, 6, 8, 10, 12, 14, 15, 17
SCR, BL, 2, 3, 4, 6, 8, 10, 12, 14, 15, 17
SCR, BL, 4, 8, 12, 17
SCR, BL, 2, 3, 4, 6, 8, 10, 12, 14, 15, 17
since the last assignment during treatment.
c TLFB methodology in conjunction with a modified Form 90 (Miller, 1996) was used to assess daily drinking for the past 90 days at baseline and
Table 2. Baseline Characteristics of Patients
nMean or % SDnMean or % SD
Education (> high school)
Self-Reported Alcohol Consumptionb
Drinks per day
Drinks per drinking day
Percent days abstinent
Percent heavy drinking days
Percent very heavy drinking days (8+/10+)
Other Substance-Related Indicators
Drinker Inventory of Consequences (DrInC) score
Age onset regular drinking
Montgomery-Asberg Depression Rating Scale (MADRS) score
Hamilton Anxiety (HAM-A) score
SF-12 Mental Aggregate score
SF-12 Physical Aggregate score
Profile of Mood States (POMS) score
Clinical Institute Withdrawal Assessment of Alcohol (CIWA) score
b Reflects mean values during the 60-day period (Days 31-90) before screening.
c Marijuana use based on positive urine drug screen.
d Scale range and interpretive values are as follows:
MADRS: (0-60) 0-6 normal; 7-19 mild depression; 20-34 moderate; 35-60 severe
HAMA: (0-56) <14 normal; 14-17 mild anxiety; 18-24 mild-moderate; 35-30 moderate-severe
SF-12: (T-score 0-100) 50 normal functioning
CIWA: (0-70) >10 indicative of alcohol withdrawal
a Group mean differences are tested for significance by t-tests for independent samples for normally-distributed variables or
Wilcoxon rank-sum tests for skewed variables. Group prevalence rate differences are tested for significance via chi-square or
Fisher's exact tests.
Placebo (n=66) Levetiracetam XR (n=64)
Table 3. Treatment Outcomes: Differences between Placebo and Levetiracetam XR
Drinks per day
Drinks per drinking day
Percent heavy drinking days
Percent very heavy drinking days (8+/10+)
Percent days abstinent
OR (95% CI)b
Percent subjects abstinent
Percent subjects with no heavy drinking days
Drinker Inventory of Consequences (DrInC) score (Weeks 8, 12, 15)
Montgomery-Asberg Depression Rating Scale (MADRS) score (Weeks 8, 12, 15)
Hamilton Anxiety (HAM-A) score (Weeks 8, 12, 15)
Profile of Mood States (POMS) score (Week 12)c
SF-12 Physical Aggregate score (Week 15)c
SF-12 Mental Aggregate score (Week 15)c
a Unless otherwise noted, LSMEANS are based on the outcome variable (untransformed) and were obtained from a mixed model that includes only study week and treatment group. Corresponding Cohen's d and p-
values are based on the outcome variable (appropriately transformed) and were obtained from a mixed model that also includes the covariates clinical site, age, SSRI use, and the baseline value of the outcome. A
positive value for Cohen's d reflects a lower adjusted LSMEAN for the levetiracetam XR group than for the placebo group; a negative value for Cohen's d reflects a higher adjusted LSMEAN for the levetiracetam XR
group than for the placebo group.
Placebo Levetiracetam XR
95% CI95% CI
c For the POMS and SF-12 outcomes, unadjusted means are presented on the untransformed variables. Corresponding Cohen's d and p-values are based on the outcome variables (appropriately transformed) and
were obtained from a general linear model that includes the covariates clinical site, age, SSRI use, and the baseline value of the outcome.
Abbreviations: LSMEAN = least square means; SE = standard error; 95% CI = 95% confidence interval; OR = odds ratio; n= numerator sample size; denom = denominator sample size.
95% CI 95% CI
b Odds ratios and corresponding p-values are derived from a logistic regression model that includes the covariates clinical site, age, SSRI use, and baseline drinking. For the outcome percent subjects abstinent,
percent days abstinent was used as the baseline drinking covariate. For the outcome percent subjects with no heavy drinking days, percent heavy drinking days was used as the baseline drinking covariate.
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Table 4. Adverse Events Occurring in at Least 10% of Patients
Number (%) of Patients with Adverse
5 (7.7) 10 (15.6) 0.181
a Computed among patients that received at least one dose of study
medication; one patient in the placebo group did not receive study
b Group prevalence rates are tested for significance via chi-square or
Fisher's exact tests.