Understanding Treatment Response With Naltrexone Among White Alcoholics (DEFINE II)

Defining an Endopheneotype for Alcohol Treatment With Naltrexone

This is a study involving treatment for alcohol dependence among males of European or Asian decent. The ultimate aim of this line of investigation is to further establish a genetic link between alcohol dependence and treatment by defining an endophenotype associated with treatment response. The study consists of two inpatient alcohol challenge sessions with treatment using random assignment to either naltrexone or placebo.

Study Overview

• Status: Completed
• Conditions: Alcoholism
• Intervention / Treatment: Drug: Placebo Oral Tablet; Drug: Naltrexone

Detailed Description

Despite the well-established efficacy of naltrexone, there are significant variations in individual responses to naltrexone. A critical question remains: under what circumstances and for which patients will naltrexone be most beneficial? Recent work at our center provides evidence that the mu-opioid receptor (OPRM1) gene polymorphism A118G (Asn40Asp) imparts a significant change in treatment response. We have shown that patients with Asn40 variant (absence of heavy drinking -73.9% v/s 49% response). To further consolidate our knowledge, we wish to test the relationship between A118G polymorphism and the subjective/objective measures to alcohol among alcoholics treated with naltrexone. This work is focused on subjects of European or Asian decent as the A118G polymorphism occurs in less than 1% of those of African decent.

Up to 40 subjects will be recruited. The subjects were admitted to the UPenn Translational Research Center and receive two alcohol challenge sessions after pretreatment with naltrexone or placebo.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 64 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

1. Males 21 years of age or older of European or Asian decent.
2. Has a current DSM IV diagnosis of alcohol dependence as determined by the Structural Clinical Interview for DSM IV (SCID-IV Mini).
3. Drank an average of 21 drinks/week in the 60 days prior to treatment and had at least 2 occasions of heavy drinking (5 or more drinks on a given day for men), as measured by the Timeline Followback (TLFB).
4. Has adequate vision, hearing, and ability to communicate to allow study participation.
5. Successfully completes detoxification as manifested by at least 48 consecutive hours of no self-reported alcohol use immediately prior to admission to the inpatient unit.
6. Has signed a witnessed informed consent
7. Scores below an 8 on the Clinical Inventory of Withdrawal for Alcohol (CIWA) prior to starting naltrexone/placebo; and 8) Can speak, print, and understand English.

Exclusion Criteria:

1. Meets DSM-IV criteria for dependence on any substance other than alcohol or nicotine in the last 6 months.
2. Tests positive on the urine drug screen for opioids, cocaine, or amphetamine at the screening visit (only 1 repeat test permitted).
3. Meets current or lifetime DSM-IV criteria for bipolar affective disorder, schizophrenia, or any psychotic disorder
4. The presence of unstable or serious medical illness, including history of stroke, seizure disorder, severe liver disease (AST or ALT > 5x normal at the time of randomization), or unstable cardiac disease
5. Has taken any psychotropic medications (including disulfiram) regularly within the last seven days prior to randomization (14 days for fluoxetine) or needs immediate treatment with a psychotropic medication (with the exception of detoxification medications or benadryl used sparingly for sleep)
6. Over age 64 and has evidence of severe cognitive impairment as evidenced by a Mini-mental status exam (MMSE) score <24
7. Has suicidal or homicidal ideation necessitating inpatient hospitalization
8. Has been abstinent more than 14 days prior to Phase 1
9. Is of African Descent
10. Meets current DSM-IV criteria for for major depression (non-substance induced), PTSD, or panic disorder.
11. Has significant hematological, pulmonary, endocrine, cardiovascular, renal, or gastrointestinal disease.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Group 1 Asn40 Placebo Placebo; Each alcohol session preceded by pretreatment with placebo oral tablet	Drug: Placebo Oral Tablet; Placebo pill; Other Names: Placebo
ACTIVE_COMPARATOR: Group 2 Asn40 Placebo Naltrexone; The first alcohol session preceded by pretreatment with placebo oral tablet. The second alcohol session preceded by pretreatment with naltrexone 50 mg as a single dose.	Drug: Placebo Oral Tablet; Placebo pill; Other Names: Placebo; Drug: Naltrexone; 50 mg of naltrexone prior to challenge session
PLACEBO_COMPARATOR: Group 3 Asp40 Placebo Placebo; Each alcohol session preceded by pretreatment with placebo oral tablet	Drug: Placebo Oral Tablet; Placebo pill; Other Names: Placebo
ACTIVE_COMPARATOR: Group 4 Asp40 Placebo Naltrexone; The first alcohol session preceded by pretreatment with placebo oral tablet. The second alcohol session preceded by pretreatment with naltrexone 50 mg as a single dose.	Drug: Placebo Oral Tablet; Placebo pill; Other Names: Placebo; Drug: Naltrexone; 50 mg of naltrexone prior to challenge session

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biphasic Alcohol Effects Scale:Total Mood	Change from baseline to peak cortisol response, during the 2nd alcohol challenge session, subjective response as measured by Biphasic Alcohol Effects Scale: Total Mood. Biphasic Alcohol Effects Scale: Total Mood: minimum = 0, maximum = 106, higher scores indicate better outcomes.	during 2nd alcohol challenge session

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adrenocorticotropic Hormone (ACTH) Levels	Change from baseline to peak cortisol response during the 2nd alcohol challenge session, objective response as measured by Adrenocorticotropic hormone (ACTH).	during 2nd alcohol challenge session

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: David Oslin, M.D., University of Pennsylvania

Study record dates

Study Major Dates

• Study Start: December 1, 2007
• Primary Completion (ACTUAL): April 1, 2010
• Study Completion (ACTUAL): June 1, 2010

Study Registration Dates

• First Submitted: January 5, 2009
• First Submitted That Met QC Criteria: January 5, 2009
• First Posted (ESTIMATE): January 6, 2009

Study Record Updates

• Last Update Posted (ACTUAL): November 21, 2019
• Last Update Submitted That Met QC Criteria: October 28, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Alcoholism; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Alcohol Deterrents; Naltrexone
• Other Study ID Numbers: 806019

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO