ABT-436 for Alcohol Dependence

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

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.

Study Overview

• Status: Completed
• Conditions: Alcohol Dependence; Alcoholism; Alcohol Use Disorders; Alcohol Abuse
• Intervention / Treatment: Drug: Matched Placebo - Sugar Pill; Drug: ABT-436

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • Johns Hopkins University School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Quincy, Massachusetts, United States
      • Boston Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Virginia
    • Charlottesville, Virginia, United States, 22911
      • University of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. Current, past, or lifetime diagnosis of psychotic disorders (note schizophrenia is diagnosed under the psychotic disorder module of the MINI)
  2. Current or past diagnosis of bipolar disorder,
  3. Current or past year major depressive episode,
  4. Current (past 3 months) eating disorder (anorexia or bulimia), or
  5. Current (within past year) diagnosis of panic disorder with or without agoraphobia,
  6. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Sugar Pill; Matched Placebo sugar pill - target dose 2 pills BID	Drug: Matched Placebo - Sugar Pill; Target Dose - 2 pills BID
ACTIVE_COMPARATOR: ABT-436; ABT-436 Target dose of 400 mg BID	Drug: ABT-436; Target dose - 400mg BID

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
• Collaborators: AbbVie
• Investigators: Principal Investigator: Raye Litten, PHD, National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (ACTUAL): May 1, 2015
• Study Completion (ACTUAL): July 1, 2015

Study Registration Dates

• First Submitted: June 4, 2012
• First Submitted That Met QC Criteria: June 4, 2012
• First Posted (ESTIMATE): June 6, 2012

Study Record Updates

• Last Update Posted (ACTUAL): April 4, 2017
• Last Update Submitted That Met QC Criteria: February 15, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Alcohol Dependence; Alcohol; Alcoholism; Alcohol Abuse; Alcohol Use Disorders
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Alcohol Drinking; Alcoholism
• Other Study ID Numbers: NCIG-004