Doxazosin an a1 Antagonist for Alcohol Dependence

Early Phase 1CompletedNCT01437046

Brown University41 enrolled

Overview

Norepinephrine system represents an important treatment target for alcohol dependence (AD) and the α1 -blocker prazosin may reduce alcohol drinking in rodents and alcoholic patients. The α1 -blocker doxazosin demonstrates a more favorable pharmacokinetic profile than prazosin, but has never been studied for AD. A double-blind placebo-controlled randomized clinical trial was designed in AD individuals seeking outpatient treatment. Doxazosin or matched placebo was titrated to 16 mg/day (or maximum tolerable dose). Drinks per week (DPW) and heavy drinking days (HDD) per week were the primary outcomes. Family history density of alcoholism (FHDA), severity of AD and gender were a priori moderators.

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 Type

Interventions

DoxazosinDRUG

Doxazosin were prepared as opaque capsules by a compounding pharmacy and inserted into blister packs. Consistent with the recommended titration, doxazosin was titrated up to 16 mg daily (or maximum tolerable dose) during the first 4 weeks. A 1-week downward titration for safety reasons was also planned. Study medication adherence was assessed by self-report and pill count. Additionally, capsules contained 25mg riboflavin as a marker of adherence through urine sample.

PlaceboDRUG

Matched placebo were prepared as opaque capsules by a compounding pharmacy and inserted into blister packs. Consistent with the recommended titration, doxazosin or matched placebo was titrated up to 16 mg daily (or maximum tolerable dose) during the first 4 weeks. A 1-week downward titration for safety reasons was also planned. Study medication adherence was assessed by self-report and pill count. Additionally, capsules contained 25mg riboflavin as a marker of adherence through urine sample.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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).

Time frame: 16 weeks

drinks per week (DPW)

whether doxazosin, as compared to placebo, decreases the number of drinks per week (DPW), measured by the TLFB

Time frame: 16 weeks

Secondary Outcomes

alcohol craving

whether doxazosin, as compared to placebo, results in diminished alcohol craving, as measured by the Obsessive Compulsive Drinking Scale (OCDS)

Time frame: 16 weeks

anxiety

whether doxazosin, as compared to placebo, results in diminished anxiety scores, measured by the Hamilton Anxiety Scale (HAMA).

Time frame: 16 weeks

Adverse Events

whether doxazosin, as compared to placebo, increases the frequency and intensity of Adverse Events (AE).

Time frame: 16 weeks

Doxazosin an a1 Antagonist for Alcohol Dependence

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes