Doxazosin an a1 Antagonist for Alcohol Dependence

Study Overview
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Brief Summary
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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.

Official Title
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Doxazosin an a1 Antagonist for Alcohol Dependence

Conditions
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Alcohol Dependence, Anxiety

Intervention / Treatment
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* Drug: Doxazosin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Doxazosin<br>Doxazosin 16mg/day | Drug: Doxazosin<br>* Doxazosin 16mg/day<br>|
| Placebo Comparator: Placebo<br>Placeno | Drug: Placebo<br> <br> |

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alcohol drinking, Alcohol craving