Alcohol Abuse, Alcohol Dependence, Alcoholism, Alcohol Use Disorders
Conditions
Keywords
Alcohol, Alcohol Dependence, Alcohol Abuse, Alcohol Use Disorders, Alcoholism
Brief summary
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
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.
Interventions
DRUGABT-436
Target dose - 400mg BID
DRUGMatched Placebo - Sugar Pill
Target Dose - 2 pills BID
Sponsors
AbbVie
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Weekly Percentage of Heaving Drinking Days | Weeks 2-12 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sugar Pill Matched Placebo sugar pill - target dose 2 pills BID
Matched Placebo - Sugar Pill: Target Dose - 2 pills BID | 71 |
| ABT-436 ABT-436 Target dose of 400 mg BID
ABT-436: Target dose - 400mg BID | 73 |
| Total | 144 |
Baseline characteristics
| Characteristic | ABT-436 | Sugar Pill | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 73 Participants | 71 Participants | 144 Participants |
| Age, Continuous | 45.8 years STANDARD_DEVIATION 10.2 | 45.5 years STANDARD_DEVIATION 11.6 | 45.7 years STANDARD_DEVIATION 10.9 |
| Region of Enrollment United States | 73 participants | 71 participants | 144 participants |
| Sex: Female, Male Female | 27 Participants | 25 Participants | 52 Participants |
| Sex: Female, Male Male | 46 Participants | 46 Participants | 92 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 67 / 71 | 73 / 73 |
| serious Total, serious adverse events | 1 / 71 | 2 / 73 |
Outcome results
Primary
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.
Time frame: Weeks 2-12
Population: Models are based on a mITT population that included subjects who received at least one dose of medication (N=144; ABT-436=73, placebo=71). One additional placebo subject had no drinking data during the maintenance period, and one ABT-436 subject was missing data on a baseline covariate, resulting in an analyzable N=142 (ABT-436=72, placebo=70).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sugar Pill | Weekly Percentage of Heaving Drinking Days | 37.6 weekly percentage of heavy drinking days |
| ABT-436 | Weekly Percentage of Heaving Drinking Days | 31.3 weekly percentage of heavy drinking days |