Doxazosin an a1 Antagonist for Alcohol Dependence

Only three medications are approved by the Food and Drug Administration (FDA) for the treatment of alcohol dependence (AD), namely disulfiram, naltrexone tablets and injection, and acamprosate, however treatment success has been inconsistent. Thus, there exists a substantial need for discovering ways to provide more effective treatments. Pre-clinical and clinical evidence has clearly demonstrated that the noradrenergic (NE) system is involved in the neurobiology of AD, thus representing an interesting new pharmacotherapy target and the theoretical rationale for this proposal. Consistent with the concept that the NE system may represent a new pharmacological target for AD, recent studies have shown that the prototype alpha-1 NE receptor antagonist prazosin reduces alcohol drinking in different animal models. Furthermore, clinical evidence has also confirmed that prazosin appears to be efficacious in reducing alcohol consumption in alcohol-dependent individuals. While prazosin has a significant side effect profile and must be taken three times a day, no other α1-blockers have been investigated in alcohol research. Prazosin is a short-acting α1-blocker approved to treat hypertension (HTN) and benign prostatic hyperplasia (BPH). After the approval of prazosin in the 70's, other selective α1-blockers have been developed to treat HTN and/or BPH. Among them, doxazosin has shown a more manageable and safer profile than prazosin. In fact, doxazosin is a long-acting α1-blocker, thus it is taken only once/day. Doxazosin is also less likely to give hypotensive side-effects. Thus, doxazosin is more commonly used in clinical practice to treat HTN and/or BPH, than short-acting α1-blockers, such as prazosin. Poor adherence to medications and/or side-effects represent important factors limiting the effectiveness of pharmacotherapies for patients with AD. If effective for AD, doxazosin may represent a simple, manageable and safe medication, which might be more easily transferable to clinical practice. However, doxazosin has never been tested in AD. This project is a 10-week, double-blind, placebo-controlled, between-subject randomized clinical trial with doxazosin (16mg once/day) in alcohol dependent (AD) individuals. This study attempts to address whether doxazosin is an effective and safe pharmacotherapy for AD.

Study Overview

• Status: Completed
• Conditions: Alcohol Dependence; Anxiety
• Intervention / Treatment: Drug: Placebo; Drug: Doxazosin

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Brown University Center for Alcohol and Addiction Studies

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age ≥18
• females must be post-menopausal for ≥1 year, surgically sterile, or practicing a birth control before entry and throughout the study; have a negative urine pregnancy test at screening and before randomization
• good health (confirmed by medical history, physical, ECG, blood/urine labs)
• DSM-IV diagnosis of AD
• average of ≥4 drinks/d for women and ≥5 drinks/d for men during 30 days within the 90 days prior to screening
• desire to reduce or quit drinking.

Exclusion Criteria:

• females who are of child bearing potential and not practicing effective birth control
• lifetime DSM-IV diagnosis of schizophrenia, bipolar disorder, or other psychosis
• recent (past 6 months) DSM-IV diagnosis of any anxiety disorder or major depression
• in the investigators' opinion, risk of suicide (e.g. active plan, or recent attempt in last year)
• DSM-IV diagnosis of dependence on any psychoactive substance other than alcohol and nicotine
• positive urine screen for any illegal substance other than marijuana
• history of hospitalization for alcohol intoxication delirium, seizure or alcohol withdrawal delirium
• Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) score ≥10, at any assessment
• treatment with naltrexone, acamprosate, topiramate, disulfiram within 1 month prior to Wk 00
• current use of psychotropic medications or drugs that interfere with doxazosin's metabolism
• use of PDE5 inhibitor erectile dysfunction drugs (e.g. sildenafil)
• treatment with any antihypertensive drug and/or any α-blocker for BPH or sleep problems (e.g. trazodone)
• baseline hypotension
• history of allergy to any α-blocker
• contraindications to take doxazosin (history of fainting and/or syncopal attacks, heart failure, significant liver diseases)
• serious illnesses, e.g. kidney failure, epilepsy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Doxazosin; Doxazosin 16mg/day	Drug: Doxazosin; Doxazosin 16mg/day
Placebo Comparator: Placebo; Placeno	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
drinking days per week (DDW)	whether doxazosin, as compared to placebo, decreases the number of drinking days per week (DDW), as measured by the timeline follow-back (TLFB). A drink is defined as a Standard Drinking Unit (SDU).	16 weeks
drinks per week (DPW)	whether doxazosin, as compared to placebo, decreases the number of drinks per week (DPW), measured by the TLFB	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
alcohol craving	whether doxazosin, as compared to placebo, results in diminished alcohol craving, as measured by the Obsessive Compulsive Drinking Scale (OCDS)	16 weeks
anxiety	whether doxazosin, as compared to placebo, results in diminished anxiety scores, measured by the Hamilton Anxiety Scale (HAMA).	16 weeks
Adverse Events	whether doxazosin, as compared to placebo, increases the frequency and intensity of Adverse Events (AE).	16 weeks

Collaborators and Investigators

• Sponsor: Brown University
• Collaborators: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): August 1, 2013
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: September 19, 2011
• First Submitted That Met QC Criteria: September 19, 2011
• First Posted (Estimate): September 20, 2011

Study Record Updates

• Last Update Posted (Estimate): July 22, 2015
• Last Update Submitted That Met QC Criteria: July 20, 2015
• Last Verified: July 1, 2015

More Information

Terms related to this study

• Keywords: Alcohol drinking; Alcohol craving
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Alcohol-Related Disorders; Substance-Related Disorders; Alcoholism; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Doxazosin
• Other Study ID Numbers: 1101000328; 1R21AA019994-01A1 (U.S. NIH Grant/Contract)