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Papers by Daniel Falk

JAMA Psychiatry, 2019

IMPORTANCE The US Food and Drug Administration recognizes total abstinence and no heavy drinking ... more IMPORTANCE The US Food and Drug Administration recognizes total abstinence and no heavy drinking days as outcomes for pivotal pharmacotherapy trials for alcohol use disorder (AUD). Many patients have difficulty achieving these outcomes, which can discourage seeking treatment and has slowed the development of medications that affect alcohol use. OBJECTIVE To compare 2 drinking-reduction outcomes with total abstinence and no heavy drinking outcomes. DESIGN, SETTING, AND PARTICIPANTS Data were obtained from 3 multisite, randomized, placebo-controlled clinical trials of medications for treating alcohol dependence (naltrexone, varenicline, and topiramate) in adults with DSM-IV-categorized alcohol dependence. MAIN OUTCOMES AND MEASURES Within each trial, the percentage of participants in active and placebo conditions who met responder definitions of abstinence, no heavy drinking days, a WHO 1-level reduction, and a WHO 2-level reduction was computed by month with corresponding effect sizes (Cohen h). RESULTS Across the 3 trials (N = 1169; mean [SD] age, 45 [10] years; 824 [70.5%] men), the percentage of participants classified as responders during the last 4 weeks of treatment was lowest for abstinence (naltrexone, 34.7% [100 of 288]; varenicline, 7.3% [7 of 96]; topiramate, 11.7% [21 of 179]) followed by no heavy drinking days (naltrexone, 51.0% [147 of 288]; varenicline, 24.0% [23 of 96]; topiramate, 20.7% [37 of 179]), WHO 2-level reduction (naltrexone, 75.0% [216 of 288]; varenicline, 55.2% [53 of 96]; topiramate, 44.7% [80 of 179]), and WHO 1-level reduction (naltrexone, 83.3% [240 of 288]; varenicline, 69.8 [67 of 96]; topiramate, 54.7% [98 of 179]) outcomes. Standardized treatment effects observed for the WHO 2-level reduction outcomes (naltrexone, Cohen h = 0.

Drug and Alcohol Dependence, 2019

BACKGROUND Non-abstinent drinking reductions that predict improvement in how individuals feel or ... more BACKGROUND Non-abstinent drinking reductions that predict improvement in how individuals feel or function, such as the World Health Organization (WHO) drinking risk levels, may be useful outcomes in clinical trials for alcohol use disorders (AUD). METHODS Current drinkers in a U.S. national survey (n = 22,005) were interviewed in 2001-02 (Wave 1) and re-interviewed 3 years later (Wave 2). WHO drinking risk levels, a 4- level categorization system (very-high-risk, high-risk, moderate-risk, and low-risk drinkers) defined using estimated mean ethanol consumption (grams) per day in the prior 12 months, and DSM-IV depressive and anxiety disorders were assessed at both waves. Logistic regression was used to produce adjusted odds ratios (aOR) testing the associations of changes between Wave 1 and Wave 2 WHO risk levels to the presence or persistence of depression and/or anxiety disorder by each initial Wave 1 risk level. RESULTS Among Wave 1 very-high-risk drinkers, lower odds of depression and/or anxiety disorders at Wave 2 were predicted by reductions in WHO risk levels of one-, two- or three-levels (aOR = 0.42, 0.37, 0.67, p-values 0.04-<.0001), as was the persistence of depression and/or anxiety disorders among those with such disorders at Wave 1 (aOR = 0.37, 0.29, 0.51, p-values .03-<.0001). Results were less consistent for participants initially drinking at lower risk levels. CONCLUSIONS Among very-high-risk drinkers, reductions in the WHO drinking risk categories were associated with lower risk of depression and/or anxiety disorders. These results add to findings indicating reductions in WHO risk levels are a meaningful indicator of how individuals feel and function.

Alcoholism: Clinical and Experimental Research, 2018

and for the National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group (NCI... more and for the National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group (NCIG) Study Group Background: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended-release (GE-XR) (HORIZANT Ò), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). Methods: Men and women (n = 346) who met DSM-5 criteria for at least moderate AUD were recruited across 10 U.S. clinical sites. Participants received double-blind GE-XR (600 mg twice a day) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were prespecified for the last 4 weeks of the treatment period. Results: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs. 21.5, respectively, p = 0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. Conclusions: Overall, GE-XR at 600 mg twice a day did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the U.S. Food and Drug Administration for treating other medical conditions.

Alcoholism: Clinical and Experimental Research, 2018

Background-Abstinence is often the treatment aim for AUD, but this may deter individuals who pref... more Background-Abstinence is often the treatment aim for AUD, but this may deter individuals who prefer drinking-reduction goals from entering treatment, and be an overly restrictive endpoint in alcohol clinical trials. Non-abstinent drinking reductions that predict improvement in how

Alcoholism, clinical and experimental research, Feb 1, 2017

Alcoholism is a chronic relapsing disorder with complex behavioral and functional heterogeneity. ... more Alcoholism is a chronic relapsing disorder with complex behavioral and functional heterogeneity. To date, attempts to characterize subgroups of alcohol-dependent (AD) individuals have largely been focused on categorical distinctions based on behaviors such as ability to abstain, age of onset, and drinking motives, but these have failed to yield predictors of treatment response and disease course. The distinction between AD individuals who are or are not interested in treatment holds significant implications for interpreting results of human laboratory studies with nontreatment seekers and clinical trials with treatment-seeking AD patients. However, despite their crucial role in alcohol-related research, these 2 groups are poorly defined. In this exploratory analysis, we attempt to better define the phenotypic differences between these 2 experimentally relevant populations. We analyzed data from AD individuals who participated in screening protocols to evaluate their suitability for ...

The lancet. Psychiatry, Jan 26, 2017

Alcohol dependence is often untreated. Although abstinence is often the aim of treatment, many dr... more Alcohol dependence is often untreated. Although abstinence is often the aim of treatment, many drinkers prefer drinking reduction goals. Therefore, if supported by evidence of benefit, drinking reduction goals could broaden the appeal of treatment. Regulatory agencies are considering non-abstinent outcomes as efficacy indicators in clinical trials, including reduction in WHO drinking risk levels-very high, high, moderate, and low-defined in terms of mean ethanol consumption (in grams) per day. We aimed to study the relationship between reductions in WHO drinking risk levels and subsequent reduction in the risk of alcohol dependence. In this population-based cohort study, we included data from 22 005 drinkers who were interviewed in 2001-02 (Wave 1) and re-interviewed 3 years later (2004-05; Wave 2) in the US National Epidemiologic Survey on Alcohol and Related Conditions. Alcohol consumption (WHO drinking risk levels) and alcohol dependence (at least three of seven DSM-IV criteria i...

Alcoholism, clinical and experimental research, 2017

Alcohol use disorder (AUD) is a highly prevalent public health problem associated with considerab... more Alcohol use disorder (AUD) is a highly prevalent public health problem associated with considerable individual and societal costs. Abstinence from alcohol is the most widely accepted target of treatment for AUD, but it severely limits treatment options and could deter individuals who prefer to reduce their drinking from seeking treatment. Clinical validation of reduced alcohol consumption as the primary outcome of alcohol clinical trials is critical for expanding treatment options. One potentially useful measure of alcohol treatment outcome is a reduction in the World Health Organization (WHO, International Guide for Monitoring Alcohol Consumption and Related Harm. Geneva, Switzerland, 2000) risk levels of alcohol use (very high risk, high risk, moderate risk, and low risk). For example, a 2-shift reduction in WHO risk levels (e.g., high risk to low risk) has been used by the European Medicines Agency (2010, Guideline on the Development of Medicinal Products for the Treatment of Alc...

Alcoholism, clinical and experimental research, Jan 10, 2017

Recently, the Food and Drug Administration (FDA) proposed to expand the options for primary endpo... more Recently, the Food and Drug Administration (FDA) proposed to expand the options for primary endpoints in the development of medications for alcohol use disorder (AUD) to include either abstinence from alcohol or a non-abstinent outcome: no heavy drinking days (with a heavy drinking day defined as more than 3 drinks per day for women and more than 4 drinks per day for men [>3/>4 cutoff]). The FDA also suggested that 6 months would be the most appropriate length for a clinical trial to demonstrate the stability of this non-abstinent drinking outcome. However, few alcohol clinical trials have examined the stability of non-heavy drinking during and after treatment. In a secondary analysis of the COMBINE study data (n=1383), we examined transitions in heavy drinking days during the course of treatment (months 1 through 4), during the transition out of treatment (months 4 through 7), and up to 12 months afterwards (months 13 through 16) using latent variable mixture models. Heavy dr...

Contemporary clinical trials, Jan 10, 2016

Placebo-controlled pharmacotherapy trials for alcohol use disorder (AUD) require an active behavi... more Placebo-controlled pharmacotherapy trials for alcohol use disorder (AUD) require an active behavioral platform to avoid putting participants at risk for untreated AUD and to better assess the effectiveness of the medication. Therapist-delivered platforms (TDP) can be costly and present a risk to study design because of the variability in therapist fidelity. Take Control is a novel computer-delivered behavioral platform developed for use in pharmacotherapy trials sponsored by the National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group (NCIG). This behavioral platform was developed with the goal of reducing trial implementation costs and limiting potential bias introduced by therapists providing TDP. This exploratory study is the first to compare Take Control with TDP on measures related to placebo response rate, medication adherence, and participant retention. Data were drawn from the placebo arms of four multisite, double-blind, randomized controlled trials ...

Alcoholism, clinical and experimental research, Jan 17, 2016

For more than 25 years, advances have been made in developing medications to treat alcohol use di... more For more than 25 years, advances have been made in developing medications to treat alcohol use disorder (AUD), highlighted by the U.S. Food and Drug Administration's approval of naltrexone (oral and long-acting) and acamprosate. Despite this progress, more work remains to be done in this area because these medications, although effective for some people, do not work for everyone. A high priority for the National Institute on Alcohol Abuse and Alcohol is to put into place a solid infrastructure to aid in the development of medications that are more effective than those currently available and with few side effects. Medication development, especially for a disorder as complex as AUD, is challenging and involves multiple phases, including discovery of "druggable" targets, preclinical studies, human clinical trials, and the adoption and implementation of the new medication into mainstream medicine. A successful medications development program requires clearly established g...

Alcoholism, clinical and experimental research, Jul 2, 2016

Missing data are common in alcohol clinical trials for both continuous and binary end points. App... more Missing data are common in alcohol clinical trials for both continuous and binary end points. Approaches to handle missing data have been explored for continuous outcomes, yet no studies have compared missing data approaches for binary outcomes (e.g., abstinence, no heavy drinking days). This study compares approaches to modeling binary outcomes with missing data in the COMBINE study. We included participants in the COMBINE study who had complete drinking data during treatment and who were assigned to active medication or placebo conditions (N = 1,146). Using simulation methods, missing data were introduced under common scenarios with varying sample sizes and amounts of missing data. Logistic regression was used to estimate the effect of naltrexone (vs. placebo) in predicting any drinking and any heavy drinking outcomes at the end of treatment using 4 analytic approaches: complete case analysis (CCA), last observation carried forward (LOCF), the worst case scenario (WCS) of missing ...

Substance Abuse, 2016

Alcohol use disorder (AUD), as currently defined in the Diagnostic and Statistical Manual, 5th Ed... more Alcohol use disorder (AUD), as currently defined in the Diagnostic and Statistical Manual, 5th Edition (DSM-5), is a heterogeneous disorder stemming from a complex interaction of neurobiological, genetic, and environmental factors. As a result of this heterogeneity, there is no one treatment for AUD that will work for everyone. During the past 2 decades, efforts have been made to develop a menu of medications to give patients and clinicians more choices when seeking a therapy that is both effective and which has limited side effects. To date, 3 medications have been approved by the US Food and Drug Administration (FDA) to treat alcohol dependence: disulfiram, naltrexone, and acamprosate. In addition to these approved medications, researchers have identified new therapeutic targets and, as a result, a number of alternative medications are now being evaluated for treatment of AUD in human studies. Although not approved by the FDA for the treatment of AUD, in some cases, these alternative medications are being used off-label by clinicians for this purpose. These potential medications are reviewed here. They include nalmefene, varenicline, gabapentin, topiramate, zonisamide, baclofen, ondansetron, levetiracetam, quetiapine, aripiprazole, and serotonin reuptake inhibitors. The effectiveness of these medications has been mixedsome show good efficacy with side effects that are mild to moderate in intensity; others have mixed or promising results but are awaiting findings from ongoing studies; and still others show poor efficacy, despite promising preliminary results. Medications development remains a high priority. Key initiatives for the National Institute on Alcohol Abuse and Alcoholism (NIAAA) include supporting the discovery and development of more effective and safer medications, advancing the field of personalized medicine, and forging public and private partnerships to investigate new and more effective compounds.

Drug and Alcohol Dependence, 2016

The views expressed in this article are those of the authors, none of whom have financial conflic... more The views expressed in this article are those of the authors, none of whom have financial conflicts of interest specifically related to the issues discussed in this article. At the time of the meeting on which this article is based, several authors were employed by pharmaceutical companies and others had received consulting fees or honoraria from one or more pharmaceutical or device companies. Authors of this article who were not employed by industry or government at the time of the meeting received travel stipends, hotel accommodations, and meals during the meeting provided by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration (FDA), which has received research contracts, grants, or other revenue from the FDA, multiple pharmaceutical and device companies, and other sources. Preparation of background literature reviews and draft manuscripts was supported by ACTTION. No official endorsement by the FDA, US National Institutes of Health, or the pharmaceutical and device companies that have provided unrestricted grants to support the activities of ACTTION should be inferred. Dr. Strain's participation in this activity was as a consultant to ACTTION. All opinions expressed and implied in this activity are solely those of Dr. Strain and do not represent or reflect the views of the Johns Hopkins University or the Johns Hopkins Health System.

Journal of Studies on Alcohol and Drugs, 2014

Several defi nitions of treatment response have been proposed for alcohol clinical trials (e.g., ... more Several defi nitions of treatment response have been proposed for alcohol clinical trials (e.g., abstinence and no heavy drinking). However, each of these outcomes allows only one defi nition of successful response. In contrast, the cumulative proportion of responders analysis (CPRA) includes all of the possible drinking response cutoff points, providing a more complete picture of the therapeutic effects of a treatment. CPRA has been used to examine the effi cacy of analgesics but not alcohol pharmacotherapy. To demonstrate its potential utility, we conducted CPRA in two large alcohol treatment trials: the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) trial (naltrexone) and a multisite topiramate trial. CPRA was used to demonstrate the effi cacy of naltrexone and topiramate on continuous measures of in-treatment drinking-heavy drinking days and drinks per day-and their reductions from pretreatment. Method: All possible cutoff points were portrayed for each measure. We provide graphs to illustrate the effects of the active medications compared with placebo and examined them statistically over a number of salient drinking outcomes to evaluate their effi cacy. Results: Treatment group responder curves were not parallel across the entire range of cutoff points; rather, they separated only at lower levels of drinking. In general, effect sizes increased by 0.10-0.15 when going from the lowest drinking level cutoff (i.e., abstinence and no heavy drinking) to the cutoff associated with the maximal treatment effect. Conclusions: CPRA may be useful in designing subsequent trials and helping to illustrate for treatment providers the likelihood of treatment success given various defi nitions of a positive response. (

Journal of Addiction Medicine, 2015

Objectives-To explore if varenicline (Chantix ®) showed more efficacy in treating certain subgrou... more Objectives-To explore if varenicline (Chantix ®) showed more efficacy in treating certain subgroups of patients. In a recent multi-site trial, varenicline was shown to be effective in reducing drinking in alcohol dependent patients, both smokers and nonsmokers. Given the heterogeneity among alcohol dependent patients, secondary analyses were conducted to determine if certain subgroups responded more favorably than others to treatment with varenicline. Methods-Data were drawn from a Phase 2 randomized, double-blind, placebo-controlled multisite 13-week trial of varenicline in alcohol dependent patients (Litten et al., 2013). Seventeen moderator variables were selected for exploratory testing on the basis of theoretical and scientific interest. Results-Of the 17 moderator variables assessed, four were statistically significant, including cigarettes per day reduction, treatment drinking goal, years drinking regularly, and age of patient. Two other variables-the type of adverse events experienced by patients and the severity of alcohol-related consequences-appeared to moderate the varenicline treatment effect at borderline statistical significance. Individuals who reduced the number of cigarettes per day experienced a significant effect from varenicline in reducing drinking, whereas those who did not change or who increased their number of cigarettes observed no beneficial effect. Reviewing the moderators related to severity, varenicline appeared to have greater efficacy than placebo among less severelydependent patients. Conclusions-Varenicline appears to be more efficacious in certain subgroups, particularly in those who reduced their smoking and in the "less severe" patient. Additional studies are warranted to confirm the results of these exploratory analyses.

Alcoholism, clinical and experimental research, 2014

Attrition is common in alcohol clinical trials and the resultant loss of data represents an impor... more Attrition is common in alcohol clinical trials and the resultant loss of data represents an important methodological problem. In the absence of a simulation study, the drinking outcomes among those who are lost to follow-up are not known. Individuals who drop out of treatment and continue to provide drinking data, however, may be a reasonable proxy group for making inferences about the drinking outcomes of those lost to follow-up. We used data from the COMBINE study, a multisite, randomized clinical trial, to examine drinking during the 4 months of treatment among individuals who dropped out of treatment but continued to provide drinking data (i.e., "treatment dropouts;" n = 185). First, we estimated the observed treatment effect size for naltrexone versus placebo in a sample that included both treatment completers (n = 961) and treatment dropouts (n = 185; total N = 1,146), as well as the observed treatment effect size among just those who dropped out of treatment (n = 18...

Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism, 2006

The 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) sought to ... more The 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) sought to determine the prevalence of drinking, smoking, and associated disorders in the general population. This survey, which includes a large representative sample of the adult population of the United States, found that drinking rates were highest among young adults and declined with increasing age. Rates of smoking and co-use of alcohol and tobacco were highest among the youngest respondents and declined thereafter. Similar patterns existed for the presence of alcohol use disorders (AUDs), nicotine dependence, and comorbidity between AUDs and nicotine dependence. Among ethnic/racial groups evaluated, Whites were most likely to drink and Native Americans/Alaskan Natives were most likely to smoke and to have an AUD, nicotine dependence, or comorbid AUD and nicotine dependence. Finally, the rates of tobacco use, daily tobacco use, and nicotine dependence increased with increasing levels of alcoh...

Addiction, 2014

Aims-We use intensive longitudinal data methods to illuminate processes affecting patients' drink... more Aims-We use intensive longitudinal data methods to illuminate processes affecting patients' drinking in relation to the discontinuation of medications within an alcohol treatment study. Although previous work has focused on broad measures of medication adherence, we focus on dynamic changes in drinking both before and after patients discontinue. Design-We conducted secondary data analyses using the COMBINE study, focused on participants who discontinued medications prior to the planned end of treatment. Using an interrupted timeseries analysis, we analyzed drinking in the weeks before and after discontinuation and also studied outcomes at the end of the COMBINE follow-up. Participants-We describe the sub-sample of COMBINE participants who discontinued medications (n=450), and compare them to those who were medication adherent (n=559) and to those who discontinued but had substantial missing data (n=217). Measurements-The primary outcomes were percent days abstinent (PDA) and percent heavy drinking days (PHDD). Medication adherence data were used to approximate the date of discontinuation. Findings-For many patients, an increase in drinking starts weeks before discontinuation (PDA: F(1,4803) = 19.07, p < .001; PHDD: F(1,4804) = 8.58, p = .003) then escalates at discontinuation (PDA: F(1,446) = 5.05, p = .025; PHDD: F(1,446) = 4.52, p = .034). Among other effects, the amount of change was moderated by the reason for discontinuation (e.g., adverse event; PDA: F(2,4803) = 3.85, p = .

Neuropsychopharmacology, 2011

Although progress has been made in the treatment of alcohol use disorders, more effective treatme... more Although progress has been made in the treatment of alcohol use disorders, more effective treatments are needed. In the last 15 years, several medications have been approved for use in alcohol dependence but have only limited effectiveness and clinical acceptance. While academics have developed some 'standards' for the performance of clinical trials for alcohol dependence, they vary considerably, in the type of populations to be studied, the length of trials, salient outcome measures, and data analyses to be used (especially in the treatment of missing data). This variability impedes the commercial development of medications to treat alcohol dependence. Using a model similar to that used to develop an expert consensus for medications to improve cognitive aspects of schizophrenia (MATRICS) and in the treatment of pain (IMMPACT), a workgroup has been formed under the auspices of ACNP, known as the ACTIVE (Alcohol Clinical Trials Initiative) group, to evaluate data from completed clinical trials to develop a consensus on key issues in the conduct of clinical trials in alcohol dependence. ACTIVE consists of academic experts, industry representatives, and staff from the Food and Drug Administration, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse. This paper describes the rationale behind the effort, its history and organization, and initial key questions that have been identified as the primary focus of the workgroup. Future papers will focus on knowledge gained from the re-analysis of completed trials and provide consensus opinions regarding the performance of clinical trials that might be undertaken in the future.

Alcoholism: Clinical and Experimental Research, 2012

Background-Despite advances in the development of medications to treat alcohol dependence, few me... more 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 alcoholdependent 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

JAMA Psychiatry, 2019

IMPORTANCE The US Food and Drug Administration recognizes total abstinence and no heavy drinking ... more IMPORTANCE The US Food and Drug Administration recognizes total abstinence and no heavy drinking days as outcomes for pivotal pharmacotherapy trials for alcohol use disorder (AUD). Many patients have difficulty achieving these outcomes, which can discourage seeking treatment and has slowed the development of medications that affect alcohol use. OBJECTIVE To compare 2 drinking-reduction outcomes with total abstinence and no heavy drinking outcomes. DESIGN, SETTING, AND PARTICIPANTS Data were obtained from 3 multisite, randomized, placebo-controlled clinical trials of medications for treating alcohol dependence (naltrexone, varenicline, and topiramate) in adults with DSM-IV-categorized alcohol dependence. MAIN OUTCOMES AND MEASURES Within each trial, the percentage of participants in active and placebo conditions who met responder definitions of abstinence, no heavy drinking days, a WHO 1-level reduction, and a WHO 2-level reduction was computed by month with corresponding effect sizes (Cohen h). RESULTS Across the 3 trials (N = 1169; mean [SD] age, 45 [10] years; 824 [70.5%] men), the percentage of participants classified as responders during the last 4 weeks of treatment was lowest for abstinence (naltrexone, 34.7% [100 of 288]; varenicline, 7.3% [7 of 96]; topiramate, 11.7% [21 of 179]) followed by no heavy drinking days (naltrexone, 51.0% [147 of 288]; varenicline, 24.0% [23 of 96]; topiramate, 20.7% [37 of 179]), WHO 2-level reduction (naltrexone, 75.0% [216 of 288]; varenicline, 55.2% [53 of 96]; topiramate, 44.7% [80 of 179]), and WHO 1-level reduction (naltrexone, 83.3% [240 of 288]; varenicline, 69.8 [67 of 96]; topiramate, 54.7% [98 of 179]) outcomes. Standardized treatment effects observed for the WHO 2-level reduction outcomes (naltrexone, Cohen h = 0.

Drug and Alcohol Dependence, 2019

BACKGROUND Non-abstinent drinking reductions that predict improvement in how individuals feel or ... more BACKGROUND Non-abstinent drinking reductions that predict improvement in how individuals feel or function, such as the World Health Organization (WHO) drinking risk levels, may be useful outcomes in clinical trials for alcohol use disorders (AUD). METHODS Current drinkers in a U.S. national survey (n = 22,005) were interviewed in 2001-02 (Wave 1) and re-interviewed 3 years later (Wave 2). WHO drinking risk levels, a 4- level categorization system (very-high-risk, high-risk, moderate-risk, and low-risk drinkers) defined using estimated mean ethanol consumption (grams) per day in the prior 12 months, and DSM-IV depressive and anxiety disorders were assessed at both waves. Logistic regression was used to produce adjusted odds ratios (aOR) testing the associations of changes between Wave 1 and Wave 2 WHO risk levels to the presence or persistence of depression and/or anxiety disorder by each initial Wave 1 risk level. RESULTS Among Wave 1 very-high-risk drinkers, lower odds of depression and/or anxiety disorders at Wave 2 were predicted by reductions in WHO risk levels of one-, two- or three-levels (aOR = 0.42, 0.37, 0.67, p-values 0.04-<.0001), as was the persistence of depression and/or anxiety disorders among those with such disorders at Wave 1 (aOR = 0.37, 0.29, 0.51, p-values .03-<.0001). Results were less consistent for participants initially drinking at lower risk levels. CONCLUSIONS Among very-high-risk drinkers, reductions in the WHO drinking risk categories were associated with lower risk of depression and/or anxiety disorders. These results add to findings indicating reductions in WHO risk levels are a meaningful indicator of how individuals feel and function.

Alcoholism: Clinical and Experimental Research, 2018

and for the National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group (NCI... more and for the National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group (NCIG) Study Group Background: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended-release (GE-XR) (HORIZANT Ò), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). Methods: Men and women (n = 346) who met DSM-5 criteria for at least moderate AUD were recruited across 10 U.S. clinical sites. Participants received double-blind GE-XR (600 mg twice a day) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were prespecified for the last 4 weeks of the treatment period. Results: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs. 21.5, respectively, p = 0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. Conclusions: Overall, GE-XR at 600 mg twice a day did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the U.S. Food and Drug Administration for treating other medical conditions.

Alcoholism: Clinical and Experimental Research, 2018

Background-Abstinence is often the treatment aim for AUD, but this may deter individuals who pref... more Background-Abstinence is often the treatment aim for AUD, but this may deter individuals who prefer drinking-reduction goals from entering treatment, and be an overly restrictive endpoint in alcohol clinical trials. Non-abstinent drinking reductions that predict improvement in how

Alcoholism, clinical and experimental research, Feb 1, 2017

Alcoholism is a chronic relapsing disorder with complex behavioral and functional heterogeneity. ... more Alcoholism is a chronic relapsing disorder with complex behavioral and functional heterogeneity. To date, attempts to characterize subgroups of alcohol-dependent (AD) individuals have largely been focused on categorical distinctions based on behaviors such as ability to abstain, age of onset, and drinking motives, but these have failed to yield predictors of treatment response and disease course. The distinction between AD individuals who are or are not interested in treatment holds significant implications for interpreting results of human laboratory studies with nontreatment seekers and clinical trials with treatment-seeking AD patients. However, despite their crucial role in alcohol-related research, these 2 groups are poorly defined. In this exploratory analysis, we attempt to better define the phenotypic differences between these 2 experimentally relevant populations. We analyzed data from AD individuals who participated in screening protocols to evaluate their suitability for ...

The lancet. Psychiatry, Jan 26, 2017

Alcohol dependence is often untreated. Although abstinence is often the aim of treatment, many dr... more Alcohol dependence is often untreated. Although abstinence is often the aim of treatment, many drinkers prefer drinking reduction goals. Therefore, if supported by evidence of benefit, drinking reduction goals could broaden the appeal of treatment. Regulatory agencies are considering non-abstinent outcomes as efficacy indicators in clinical trials, including reduction in WHO drinking risk levels-very high, high, moderate, and low-defined in terms of mean ethanol consumption (in grams) per day. We aimed to study the relationship between reductions in WHO drinking risk levels and subsequent reduction in the risk of alcohol dependence. In this population-based cohort study, we included data from 22 005 drinkers who were interviewed in 2001-02 (Wave 1) and re-interviewed 3 years later (2004-05; Wave 2) in the US National Epidemiologic Survey on Alcohol and Related Conditions. Alcohol consumption (WHO drinking risk levels) and alcohol dependence (at least three of seven DSM-IV criteria i...

Alcoholism, clinical and experimental research, 2017

Alcohol use disorder (AUD) is a highly prevalent public health problem associated with considerab... more Alcohol use disorder (AUD) is a highly prevalent public health problem associated with considerable individual and societal costs. Abstinence from alcohol is the most widely accepted target of treatment for AUD, but it severely limits treatment options and could deter individuals who prefer to reduce their drinking from seeking treatment. Clinical validation of reduced alcohol consumption as the primary outcome of alcohol clinical trials is critical for expanding treatment options. One potentially useful measure of alcohol treatment outcome is a reduction in the World Health Organization (WHO, International Guide for Monitoring Alcohol Consumption and Related Harm. Geneva, Switzerland, 2000) risk levels of alcohol use (very high risk, high risk, moderate risk, and low risk). For example, a 2-shift reduction in WHO risk levels (e.g., high risk to low risk) has been used by the European Medicines Agency (2010, Guideline on the Development of Medicinal Products for the Treatment of Alc...

Alcoholism, clinical and experimental research, Jan 10, 2017

Recently, the Food and Drug Administration (FDA) proposed to expand the options for primary endpo... more Recently, the Food and Drug Administration (FDA) proposed to expand the options for primary endpoints in the development of medications for alcohol use disorder (AUD) to include either abstinence from alcohol or a non-abstinent outcome: no heavy drinking days (with a heavy drinking day defined as more than 3 drinks per day for women and more than 4 drinks per day for men [>3/>4 cutoff]). The FDA also suggested that 6 months would be the most appropriate length for a clinical trial to demonstrate the stability of this non-abstinent drinking outcome. However, few alcohol clinical trials have examined the stability of non-heavy drinking during and after treatment. In a secondary analysis of the COMBINE study data (n=1383), we examined transitions in heavy drinking days during the course of treatment (months 1 through 4), during the transition out of treatment (months 4 through 7), and up to 12 months afterwards (months 13 through 16) using latent variable mixture models. Heavy dr...

Contemporary clinical trials, Jan 10, 2016

Placebo-controlled pharmacotherapy trials for alcohol use disorder (AUD) require an active behavi... more Placebo-controlled pharmacotherapy trials for alcohol use disorder (AUD) require an active behavioral platform to avoid putting participants at risk for untreated AUD and to better assess the effectiveness of the medication. Therapist-delivered platforms (TDP) can be costly and present a risk to study design because of the variability in therapist fidelity. Take Control is a novel computer-delivered behavioral platform developed for use in pharmacotherapy trials sponsored by the National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group (NCIG). This behavioral platform was developed with the goal of reducing trial implementation costs and limiting potential bias introduced by therapists providing TDP. This exploratory study is the first to compare Take Control with TDP on measures related to placebo response rate, medication adherence, and participant retention. Data were drawn from the placebo arms of four multisite, double-blind, randomized controlled trials ...

Alcoholism, clinical and experimental research, Jan 17, 2016

For more than 25 years, advances have been made in developing medications to treat alcohol use di... more For more than 25 years, advances have been made in developing medications to treat alcohol use disorder (AUD), highlighted by the U.S. Food and Drug Administration's approval of naltrexone (oral and long-acting) and acamprosate. Despite this progress, more work remains to be done in this area because these medications, although effective for some people, do not work for everyone. A high priority for the National Institute on Alcohol Abuse and Alcohol is to put into place a solid infrastructure to aid in the development of medications that are more effective than those currently available and with few side effects. Medication development, especially for a disorder as complex as AUD, is challenging and involves multiple phases, including discovery of "druggable" targets, preclinical studies, human clinical trials, and the adoption and implementation of the new medication into mainstream medicine. A successful medications development program requires clearly established g...

Alcoholism, clinical and experimental research, Jul 2, 2016

Missing data are common in alcohol clinical trials for both continuous and binary end points. App... more Missing data are common in alcohol clinical trials for both continuous and binary end points. Approaches to handle missing data have been explored for continuous outcomes, yet no studies have compared missing data approaches for binary outcomes (e.g., abstinence, no heavy drinking days). This study compares approaches to modeling binary outcomes with missing data in the COMBINE study. We included participants in the COMBINE study who had complete drinking data during treatment and who were assigned to active medication or placebo conditions (N = 1,146). Using simulation methods, missing data were introduced under common scenarios with varying sample sizes and amounts of missing data. Logistic regression was used to estimate the effect of naltrexone (vs. placebo) in predicting any drinking and any heavy drinking outcomes at the end of treatment using 4 analytic approaches: complete case analysis (CCA), last observation carried forward (LOCF), the worst case scenario (WCS) of missing ...

Substance Abuse, 2016

Alcohol use disorder (AUD), as currently defined in the Diagnostic and Statistical Manual, 5th Ed... more Alcohol use disorder (AUD), as currently defined in the Diagnostic and Statistical Manual, 5th Edition (DSM-5), is a heterogeneous disorder stemming from a complex interaction of neurobiological, genetic, and environmental factors. As a result of this heterogeneity, there is no one treatment for AUD that will work for everyone. During the past 2 decades, efforts have been made to develop a menu of medications to give patients and clinicians more choices when seeking a therapy that is both effective and which has limited side effects. To date, 3 medications have been approved by the US Food and Drug Administration (FDA) to treat alcohol dependence: disulfiram, naltrexone, and acamprosate. In addition to these approved medications, researchers have identified new therapeutic targets and, as a result, a number of alternative medications are now being evaluated for treatment of AUD in human studies. Although not approved by the FDA for the treatment of AUD, in some cases, these alternative medications are being used off-label by clinicians for this purpose. These potential medications are reviewed here. They include nalmefene, varenicline, gabapentin, topiramate, zonisamide, baclofen, ondansetron, levetiracetam, quetiapine, aripiprazole, and serotonin reuptake inhibitors. The effectiveness of these medications has been mixedsome show good efficacy with side effects that are mild to moderate in intensity; others have mixed or promising results but are awaiting findings from ongoing studies; and still others show poor efficacy, despite promising preliminary results. Medications development remains a high priority. Key initiatives for the National Institute on Alcohol Abuse and Alcoholism (NIAAA) include supporting the discovery and development of more effective and safer medications, advancing the field of personalized medicine, and forging public and private partnerships to investigate new and more effective compounds.

Drug and Alcohol Dependence, 2016

The views expressed in this article are those of the authors, none of whom have financial conflic... more The views expressed in this article are those of the authors, none of whom have financial conflicts of interest specifically related to the issues discussed in this article. At the time of the meeting on which this article is based, several authors were employed by pharmaceutical companies and others had received consulting fees or honoraria from one or more pharmaceutical or device companies. Authors of this article who were not employed by industry or government at the time of the meeting received travel stipends, hotel accommodations, and meals during the meeting provided by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration (FDA), which has received research contracts, grants, or other revenue from the FDA, multiple pharmaceutical and device companies, and other sources. Preparation of background literature reviews and draft manuscripts was supported by ACTTION. No official endorsement by the FDA, US National Institutes of Health, or the pharmaceutical and device companies that have provided unrestricted grants to support the activities of ACTTION should be inferred. Dr. Strain's participation in this activity was as a consultant to ACTTION. All opinions expressed and implied in this activity are solely those of Dr. Strain and do not represent or reflect the views of the Johns Hopkins University or the Johns Hopkins Health System.

Journal of Studies on Alcohol and Drugs, 2014

Several defi nitions of treatment response have been proposed for alcohol clinical trials (e.g., ... more Several defi nitions of treatment response have been proposed for alcohol clinical trials (e.g., abstinence and no heavy drinking). However, each of these outcomes allows only one defi nition of successful response. In contrast, the cumulative proportion of responders analysis (CPRA) includes all of the possible drinking response cutoff points, providing a more complete picture of the therapeutic effects of a treatment. CPRA has been used to examine the effi cacy of analgesics but not alcohol pharmacotherapy. To demonstrate its potential utility, we conducted CPRA in two large alcohol treatment trials: the COMBINE (Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence) trial (naltrexone) and a multisite topiramate trial. CPRA was used to demonstrate the effi cacy of naltrexone and topiramate on continuous measures of in-treatment drinking-heavy drinking days and drinks per day-and their reductions from pretreatment. Method: All possible cutoff points were portrayed for each measure. We provide graphs to illustrate the effects of the active medications compared with placebo and examined them statistically over a number of salient drinking outcomes to evaluate their effi cacy. Results: Treatment group responder curves were not parallel across the entire range of cutoff points; rather, they separated only at lower levels of drinking. In general, effect sizes increased by 0.10-0.15 when going from the lowest drinking level cutoff (i.e., abstinence and no heavy drinking) to the cutoff associated with the maximal treatment effect. Conclusions: CPRA may be useful in designing subsequent trials and helping to illustrate for treatment providers the likelihood of treatment success given various defi nitions of a positive response. (

Journal of Addiction Medicine, 2015

Objectives-To explore if varenicline (Chantix ®) showed more efficacy in treating certain subgrou... more Objectives-To explore if varenicline (Chantix ®) showed more efficacy in treating certain subgroups of patients. In a recent multi-site trial, varenicline was shown to be effective in reducing drinking in alcohol dependent patients, both smokers and nonsmokers. Given the heterogeneity among alcohol dependent patients, secondary analyses were conducted to determine if certain subgroups responded more favorably than others to treatment with varenicline. Methods-Data were drawn from a Phase 2 randomized, double-blind, placebo-controlled multisite 13-week trial of varenicline in alcohol dependent patients (Litten et al., 2013). Seventeen moderator variables were selected for exploratory testing on the basis of theoretical and scientific interest. Results-Of the 17 moderator variables assessed, four were statistically significant, including cigarettes per day reduction, treatment drinking goal, years drinking regularly, and age of patient. Two other variables-the type of adverse events experienced by patients and the severity of alcohol-related consequences-appeared to moderate the varenicline treatment effect at borderline statistical significance. Individuals who reduced the number of cigarettes per day experienced a significant effect from varenicline in reducing drinking, whereas those who did not change or who increased their number of cigarettes observed no beneficial effect. Reviewing the moderators related to severity, varenicline appeared to have greater efficacy than placebo among less severelydependent patients. Conclusions-Varenicline appears to be more efficacious in certain subgroups, particularly in those who reduced their smoking and in the "less severe" patient. Additional studies are warranted to confirm the results of these exploratory analyses.

Alcoholism, clinical and experimental research, 2014

Attrition is common in alcohol clinical trials and the resultant loss of data represents an impor... more Attrition is common in alcohol clinical trials and the resultant loss of data represents an important methodological problem. In the absence of a simulation study, the drinking outcomes among those who are lost to follow-up are not known. Individuals who drop out of treatment and continue to provide drinking data, however, may be a reasonable proxy group for making inferences about the drinking outcomes of those lost to follow-up. We used data from the COMBINE study, a multisite, randomized clinical trial, to examine drinking during the 4 months of treatment among individuals who dropped out of treatment but continued to provide drinking data (i.e., "treatment dropouts;" n = 185). First, we estimated the observed treatment effect size for naltrexone versus placebo in a sample that included both treatment completers (n = 961) and treatment dropouts (n = 185; total N = 1,146), as well as the observed treatment effect size among just those who dropped out of treatment (n = 18...

Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism, 2006

The 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) sought to ... more The 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) sought to determine the prevalence of drinking, smoking, and associated disorders in the general population. This survey, which includes a large representative sample of the adult population of the United States, found that drinking rates were highest among young adults and declined with increasing age. Rates of smoking and co-use of alcohol and tobacco were highest among the youngest respondents and declined thereafter. Similar patterns existed for the presence of alcohol use disorders (AUDs), nicotine dependence, and comorbidity between AUDs and nicotine dependence. Among ethnic/racial groups evaluated, Whites were most likely to drink and Native Americans/Alaskan Natives were most likely to smoke and to have an AUD, nicotine dependence, or comorbid AUD and nicotine dependence. Finally, the rates of tobacco use, daily tobacco use, and nicotine dependence increased with increasing levels of alcoh...

Addiction, 2014

Aims-We use intensive longitudinal data methods to illuminate processes affecting patients' drink... more Aims-We use intensive longitudinal data methods to illuminate processes affecting patients' drinking in relation to the discontinuation of medications within an alcohol treatment study. Although previous work has focused on broad measures of medication adherence, we focus on dynamic changes in drinking both before and after patients discontinue. Design-We conducted secondary data analyses using the COMBINE study, focused on participants who discontinued medications prior to the planned end of treatment. Using an interrupted timeseries analysis, we analyzed drinking in the weeks before and after discontinuation and also studied outcomes at the end of the COMBINE follow-up. Participants-We describe the sub-sample of COMBINE participants who discontinued medications (n=450), and compare them to those who were medication adherent (n=559) and to those who discontinued but had substantial missing data (n=217). Measurements-The primary outcomes were percent days abstinent (PDA) and percent heavy drinking days (PHDD). Medication adherence data were used to approximate the date of discontinuation. Findings-For many patients, an increase in drinking starts weeks before discontinuation (PDA: F(1,4803) = 19.07, p < .001; PHDD: F(1,4804) = 8.58, p = .003) then escalates at discontinuation (PDA: F(1,446) = 5.05, p = .025; PHDD: F(1,446) = 4.52, p = .034). Among other effects, the amount of change was moderated by the reason for discontinuation (e.g., adverse event; PDA: F(2,4803) = 3.85, p = .

Neuropsychopharmacology, 2011

Although progress has been made in the treatment of alcohol use disorders, more effective treatme... more Although progress has been made in the treatment of alcohol use disorders, more effective treatments are needed. In the last 15 years, several medications have been approved for use in alcohol dependence but have only limited effectiveness and clinical acceptance. While academics have developed some 'standards' for the performance of clinical trials for alcohol dependence, they vary considerably, in the type of populations to be studied, the length of trials, salient outcome measures, and data analyses to be used (especially in the treatment of missing data). This variability impedes the commercial development of medications to treat alcohol dependence. Using a model similar to that used to develop an expert consensus for medications to improve cognitive aspects of schizophrenia (MATRICS) and in the treatment of pain (IMMPACT), a workgroup has been formed under the auspices of ACNP, known as the ACTIVE (Alcohol Clinical Trials Initiative) group, to evaluate data from completed clinical trials to develop a consensus on key issues in the conduct of clinical trials in alcohol dependence. ACTIVE consists of academic experts, industry representatives, and staff from the Food and Drug Administration, the National Institute on Alcohol Abuse and Alcoholism, and the National Institute on Drug Abuse. This paper describes the rationale behind the effort, its history and organization, and initial key questions that have been identified as the primary focus of the workgroup. Future papers will focus on knowledge gained from the re-analysis of completed trials and provide consensus opinions regarding the performance of clinical trials that might be undertaken in the future.

Alcoholism: Clinical and Experimental Research, 2012

Background-Despite advances in the development of medications to treat alcohol dependence, few me... more 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 alcoholdependent 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