Doxazosin an a1 Antagonist for Alcohol Dependence
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Alcohol Dependence Anxiety |
Drug: Doxazosin Drug: Placebo |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator) Primary Purpose: Treatment |
| Official Title: | Doxazosin an a1 Antagonist for Alcohol Dependence |
- drinking days per week (DDW) [ Designated as safety issue: No ]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).
- drinks per week (DPW) [ Designated as safety issue: No ]whether doxazosin, as compared to placebo, decreases the number of drinks per week (DPW), measured by the TLFB
- alcohol craving [ Designated as safety issue: No ]whether doxazosin, as compared to placebo, results in diminished alcohol craving, as measured by the Obsessive Compulsive Drinking Scale (OCDS)
- anxiety [ Designated as safety issue: No ]whether doxazosin, as compared to placebo, results in diminished anxiety scores, measured by the Hamilton Anxiety Scale (HAMA).
- Adverse Events [ Designated as safety issue: Yes ]whether doxazosin, as compared to placebo, increases the frequency and intensity of Adverse Events (AE).
| Estimated Enrollment: | 60 |
| Study Start Date: | November 2011 |
| Estimated Study Completion Date: | December 2013 |
| Estimated Primary Completion Date: | August 2013 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Experimental: Doxazosin
Doxazosin 16mg/day
|
Drug: Doxazosin
Doxazosin 16mg/day
|
| Placebo Comparator: Placebo | Drug: Placebo |
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
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.
Contacts and Locations| Contact: Lorenzo Leggio, MD | 401-863-6638 |
| United States, Rhode Island | |
| Brown University Center for Alcohol and Addiction Studies | Recruiting |
| Providence, Rhode Island, United States, 02903 | |
| Contact: Lorenzo Leggio, MD 401-863-6638 | |
| Principal Investigator: Lorenzo Leggio, MD | |
| Sub-Investigator: George A. Kenna, PhD, RPh | |
| Sub-Investigator: Robert M Swift, MD, PhD | |
| Sub-Investigator: William Zywiak, PhD | |
More Information
No publications provided
| ClinicalTrials.gov Identifier: | NCT01437046 History of Changes |
| Other Study ID Numbers: | 1101000328, 1R21AA019994-01A1 |
| Study First Received: | September 19, 2011 |
| Last Updated: | February 2, 2012 |
| Health Authority: | United States: Institutional Review Board |
Keywords provided by Brown University:
|
Alcohol drinking Alcohol craving |
Additional relevant MeSH terms:
|
Alcoholism Anxiety Disorders Alcohol-Related Disorders Substance-Related Disorders Mental Disorders Doxazosin Antihypertensive Agents Cardiovascular Agents Therapeutic Uses |
Pharmacologic Actions Adrenergic alpha-1 Receptor Antagonists Adrenergic alpha-Antagonists Adrenergic Antagonists Adrenergic Agents Neurotransmitter Agents Molecular Mechanisms of Pharmacological Action Physiological Effects of Drugs |
ClinicalTrials.gov processed this record on May 16, 2013