ABT-436 for Alcohol Dependence

Study Overview
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Brief Summary
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The primary efficacy endpoint examines the hypothesis that ABT-436 will decrease the weekly percentage of heavy drinking days during Study Weeks 2 through 12 (Days 8-84) as compared to placebo. A heavy drinking day is 4 or more drinks per drinking day for women and 5 or more drinks per drinking day for men.

Detailed Description
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Adrenocorticotropic hormone (ACTH) release from the pituitary gland via V1B stimulation is central to the hypothalamus-pituitary-adrenal (HPA) axis stress response (Carrasco & Van de Kar-2003, Herman & Cullinan-1997, Sapolsky et al-2000; Tsigos & Chrousos-2002). Chronic dysregulation of the HPA axis is common in major depressive disorder, anxiety disorders, and substance abuse disorders characterized by elevated AVP, increased responsiveness to AVP, as well as either increased or decreased overall HPA axis activity or responsiveness (Dinan & Scott-2005). HPA axis normalization via pituitary V1B antagonism is a mechanism for potential ABT-436 efficacy in these disorders (Schüle et al-2009). Limbic V1B antagonism in the brain may also contribute to efficacy (Roper et al-2011). Alcohol dependence, or alcoholism, is characterized by a chronic relapsing course, in which alcohol-associated cues and stress are known relapse triggers (Brownell et al-1986, Heilig & Egli-2006, Sinha & Li-2007). Recent research suggests that neural systems mediating behavioral stress responses may offer useful targets for pharmacotherapy of alcoholism. In animal models, excessive alcohol consumption that results from a history of alcohol dependence is accompanied by increased behavioral sensitivity to stress (Heilig & Koob-2007). Preclinical studies have shown that V1B antagonists can attenuate reinstatement of heroin and alcohol self-administration, and block dependence-induced exaggeration of alcohol intake, in rats. V1B antagonists have also been shown to block stress-induced reinstatement of drug and alcohol seeking in ethanol dependent rats (Zhou-2011). For these reasons the NIAAA Clinical Investigations Group (NCIG) proposes to test ABT-436 in a Phase 2, proof of concept trial for the treatment of alcohol dependence.

Official Title
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A Phase 2, Double-Blind, Randomized, Placebo Controlled Trial to Assess the Efficacy of ABT-436 for Alcohol Dependence

Conditions
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Alcohol Dependence, Alcohol Abuse, Alcohol Use Disorders, Alcoholism

Intervention / Treatment
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* Drug: ABT-436
* Drug: Matched Placebo - Sugar Pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be at least 21 years of age and no more than 65 years of age. Have a current (past 12 months) DSM-IV-TR diagnosis of alcohol dependence. Be seeking treatment for alcohol dependence and desire a reduction or cessation of drinking. Exclusion Criteria: current (past 12 months) abuse or dependence on any psychoactive substance other than alcohol, caffeine and nicotine, including sedatives and hypnotics, as defined by DSM-IV-TR criteria. positive urine toxicology screen performed during screening or baseline. been hospitalized for alcohol intoxication delirium, alcohol withdrawal delirium, alcohol-induced persisting dementia or amnestic disorder, or have had an alcohol withdrawal seizure, alcohol-induced psychotic disorder with a primary diagnosis of alcohol dependence or a history of any seizure disorder. Have any of the following, based on DSM-IV-TR criteria as assessed using the MINI: Current, past, or lifetime diagnosis of psychotic disorders (note schizophrenia is diagnosed under the psychotic disorder module of the MINI) Current or past diagnosis of bipolar disorder, Current or past year major depressive episode, Current (past 3 months) eating disorder (anorexia or bulimia), or Current (within past year) diagnosis of panic disorder with or without agoraphobia, Anti-social personality disorder. Have any underlying medical condition that could exacerbate during trial participation causing hospitalization, surgery, and/or the need to use exclusionary medications to treat condition. Be pregnant or breast-feeding or have plans to become pregnant at any time during the study. Have a clinically significant abnormal laboratory value; Hemoglobin A1c value > 7%. Have a clinically significant ECG as determined by the investigator or abnormal ECG heart rate (<45 or > 100 bpm or QTc interval corrected for heart rate using the Fridericia formula (QTcF) > 450 msec. Have HIV or Hepatitis A, B or C.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Sugar Pill<br>Matched Placebo sugar pill - target dose 2 pills BID | Drug: Matched Placebo - Sugar Pill<br>* Target Dose - 2 pills BID<br>|
| Active Comparator: ABT-436<br>ABT-436 Target dose of 400 mg BID | Drug: ABT-436<br>* Target dose - 400mg BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Weekly Percentage of Heaving Drinking Days | The primary objective of this study is to assess the efficacy of ABT-436 to reduce the weekly percentage of heavy drinking days (reduction in drinking) in subjects with alcohol dependence confirmed by DSM-IV-TR criteria. A heavy drinking day is 4 or more drinks per drinking day for women and 5 or more drinks per drinking day for men. The outcome measure was averaged across weeks 2-12. | Weeks 2-12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alcohol, Alcohol Dependence, Alcohol Abuse, Alcohol Use Disorders, Alcoholism