Prazosin and Naltrexone (PaN) Study for Veterans With Alcohol Use Disorders

NCT02322047 | Completed Phase 2 Results DMC

• 1 other identifier: W81XWH-14-1-0025
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to evaluate whether the combination of prazosin and naltrexone will decrease alcohol cravings and drinking in individuals who have problems with alcohol and have used alcohol at risky levels compare to naltrexone and placebo (Nal/Pl), prazosin and placebo (Praz/Pl), and double-placebo (Pl/Pl). We hypothesize that those assigned to both prazosin and naltrexone would report significantly greater decreases in percent drinking days and heavy drinking days as well as significantly greater reduction in craving from pre to post-treatment than those assigned to either single medication or double-placebo. Prazosin is a medication that is approved by the U.S. Food and Drug Administration (FDA) to treat people with high blood pressure. Some studies have shown that prazosin may also decrease nightmares and improve sleep in Veterans suffering from Posttraumatic Stress Disorder (PTSD). Animal studies have consistently found that prazosin is associated with decreased alcohol consumption and that the combination of prazosin and naltrexone outperforms either medication alone. The current study is evaluating an "off-label" use of prazosin to determine whether it is helpful in decreasing alcohol cravings and consumption among people with alcohol problems. "Off-label" means that the FDA has not approved the use of prazosin for alcohol problems. Naltrexone is a medication that is FDA approved for treating alcohol problems. This study is sponsored by the Department of Defense and the Congressionally Directed Medical Research Program (DoD/CDMRP). We expect approximately 120 participants in this study, which will run over approximately 4 years. Study participants will be involved in the study for 7 weeks, or until they complete the Final Assessment.

Conditions

Alcohol Use Disorder; Posttraumatic Stress Disorder (PTSD)

Keywords

Alcohol Drinking; Craving; Drinking Behavior; Prazosin; Naltrexone; Adrenergic Alpha-1 Receptor Antagonists; Adrenergic Antagonists; Adrenergic Alpha-Antagonists; mu-Opioid Receptor Antagonist; Opioid Antagonist; Alcohol Use Disorder; Posttraumatic Stress Disorder; PTSD; Alcohol Treatment; Alcohol Dependence; Pharmacology Treatment; AUD; Alcohol Abuse; Substance Use Disorder; SUD; Substance Abuse; Addiction; Alcohol Addiction; Substance Addiction; Substance Dependence

Outcome Measures

Primary Outcomes (3)

• Change in Percent Drinking Days (PDD) (Visit 8 PDD - Visit 2 PDD)

  PDD was calculated based on self-reported drinking history collected via Form-90. Drinking days were defined as days when participants consumed alcohol. Form-90 was completed by participants in visit 2 (baseline) and visit 8 (last visit). Form-90 collected in the baseline visit recorded participants' alcohol consumption from 90 days prior to their baseline visit until the day before their baseline visit. Form-90 collected in the last visit recorded participants' alcohol consumption from baseline until the day before their last visit. This outcome measures changes in PDD between visit 8 and visit 2. Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days. The outliers were due to scheduling difficulties.

  Visit 2 (baseline) and visit 8 (last visit). Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days due to scheduling difficulties.

• Change in Percent Heavy Drinking Days (PHDD) (Visit 8 PHDD - Visit 2 PHDD)

  PHDD was calculated based on self-reported drinking history collected via Form-90. Heavy drinking days were defined as days when participants consumed 4 or more drinks for females and 5 or more drinks for males. Form-90 was completed by participants in the baseline and last visit. Form-90 collected in the baseline visit recorded participants' alcohol consumption 90 days prior to their baseline visit. Form-90 collected in the last visit recorded participants' alcohol consumption from baseline until the day before their last visit. This outcome measures changes in PHDD between visit 8 and visit 2. Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days. The outliers were due to scheduling difficulties.

  Visit 2 (baseline) and Visit 8 (last visit). Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days due to scheduling difficulties.

• Change in Alcohol Craving (Visit 8 PACS - Visit 2 PACS)

  Alcohol craving was assessed in visit 2 (baseline) and the last visit (visit 8) using the Pennsylvania Alcohol Craving Scale (PACS). The PACS had 5 questions, where each question had six options presented in Likert Scales from 0 to 6, with 0 being the least and 6 being the highest possible option, thus the possible minimum and maximum values are 0 and 30, respectively. Higher scores mean higher craving. This outcome measures the change in PACS scores between visits 2 and 8 (visit 8 PACS score - visit 2 PACS score). Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days. The outliers were due to scheduling difficulties.

  Visit 2 (baseline) and visit 8 (last visit). Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days due to scheduling difficulties.

Secondary Outcomes (1)

• Change in Mean Drinks Per Day of Drinking (Visit 8 - Visit 2)

  Visit 2 (baseline) and visit 8 (last visit). Per the protocol, visit 8 is scheduled to occur 42 days (± 7days) after visit 2. In reality, visit 8 occurred 35 to 76 days after visit 2 with the average of 45 days due to scheduling difficulties.

Study Arms (4)

Praz/Nal

EXPERIMENTAL

Prazosin and Naltrexone. Prazosin will be taken following this titration schedule: Days 1-2: 1 mg @ 9PM Days 3-4: 1 mg @ 9AM, 3PM, 9PM Days 5-7: 2 mg @ 9AM, 3PM, 9PM Days 8-10: 2mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 11-14: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 15-42: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Naltrexone will be taken from day 1 to day 42 at 9 PM. Dose: 50 mg.

Drug: Prazosin; Drug: Naltrexone

Praz/Pl

ACTIVE COMPARATOR

Prazosin and Placebo (Naltrexone) Prazosin will be taken following this titration schedule: Days 1-2: 1 mg @ 9PM Days 3-4: 1 mg @ 9AM, 3PM, 9PM Days 5-7: 2 mg @ 9AM, 3PM, 9PM Days 8-10: 2mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 11-14: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 15-42: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Naltrexone Placebo will be taken from day 1 to day 42 at 9 PM. Dose: 50 mg.

Drug: Prazosin; Drug: Placebo (Naltrexone)

Nal/Pl

ACTIVE COMPARATOR

Naltrexone and Placebo (Prazosin) Prazosin Placebo will be taken following this titration schedule: Days 1-2: 1 mg @ 9PM Days 3-4: 1 mg @ 9AM, 3PM, 9PM Days 5-7: 2 mg @ 9AM, 3PM, 9PM Days 8-10: 2mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 11-14: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 15-42: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Naltrexone will be taken from day 1 to day 42 at 9 PM. Dose: 50 mg.

Drug: Naltrexone; Drug: Placebo (Prazosin)

Pl/Pl

PLACEBO COMPARATOR

Placebo (Prazosin) and Placebo (Naltrexone) Prazosin Placebo will be taken following this titration schedule: Days 1-2: 1 mg @ 9PM Days 3-4: 1 mg @ 9AM, 3PM, 9PM Days 5-7: 2 mg @ 9AM, 3PM, 9PM Days 8-10: 2mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 11-14: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 15-42: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Naltrexone Placebo will be taken from day 1 to day 42 at 9 PM. Dose: 50 mg.

Drug: Placebo (Prazosin); Drug: Placebo (Naltrexone)

Interventions

Prazosin DRUG

Prazosin Dosing Days 1-2: 1 mg @ 9PM Days 3-4: 1 mg @ 9AM, 3PM, 9PM Days 5-7: 2 mg @ 9AM, 3PM, 9PM Days 8-10: 2mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 11-14: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 15-42: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM

Also known as: Minipress

Praz/Nal; Praz/Pl

Naltrexone DRUG

Naltrexone Dosing Days 1-42: 50mg @ 9PM

Nal/Pl; Praz/Nal

Placebo (Prazosin) DRUG

Placebo Dosing Days 1-2: 1 mg @ 9PM Days 3-4: 1 mg @ 9AM, 3PM, 9PM Days 5-7: 2 mg @ 9AM, 3PM, 9PM Days 8-10: 2mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 11-14: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM Days 15-42: 4mg @ 9 AM, 3 PM; 8mg @ 9 PM

Also known as: Placebo

Nal/Pl; Pl/Pl

Placebo (Naltrexone) DRUG

Placebo Dosing Days 1-42: 50mg @ 9PM

Also known as: Placebo

Pl/Pl; Praz/Pl

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Veteran of the U.S. military or National Guard Reserve.
• Current AUD by DSM-5 criteria.
• Heavy drinking (\>14 drinks per week for females; \> 21 drinks per week for males) for at least 2 weeks in the last 3 months and some drinking during the past two weeks OR binge drinking for at least 3 days in the last month (4+ drinks for females; 5+ drinks for males).
• At least mild alcohol craving as assessed by the Pennsylvania Alcohol Craving Scale (PACS; score \> 10) at baseline.
• Age 18-80.
• English fluency and literacy.
• Trying or planning to try to cut down on or abstain from alcohol.
• Good general medical health.
• Capable of giving informed consent.

You may not qualify if:

• Uncontrolled psychiatric disorder with psychotic symptoms or cognitive impairment.
• If taking psychiatric medication, NOT on a stable dose for at least 30 days prior to randomization.
• Any suicidal ideation in the past 7 days, plan or intent past 6 months, or any suicide attempt past year.
• Homicidal ideation with plan and intent in the past 30 days.
• Patient Health Questionnaire-9 (PHQ-9) endorsement of hopelessness or self-harm/SI and/or sum scale score ≥ 19.
• Any use of prazosin or naltrexone past 30 days.
• Currently taking disulfiram or acamprosate OR planning to take any of these medications (including prazosin or naltrexone) during the study.
• Current moderate or severe substance use disorder (past 30 days) on any psychoactive substance other than alcohol, nicotine, or cannabis, OR use of any amphetamine or opioid-containing medications during the previous 30 days.
• Significant acute or chronic medical illness
• Preexisting hypotension (sys \<100) or orthostatic hypotension (systolic drop of \> 20 mmHg; after two minutes of standing, or any drop with dizziness).
• Allergy or previous adverse reaction to naltrexone, prazosin, quinazolines, or other α-1 adrenergic blockers or use of other α -1 adrenergic blocker.
• Women who are pregnant, breastfeeding, or of childbearing potential and not using a contraceptive method judged by the investigator to be effective.
• Legal involvement that could interfere with study participation, including being court ordered for treatment.
• Signs or symptoms of withdrawal at time of initial consent.
• Any participation in an experimental drug study or any addiction study past 30 days.

Sponsors & Collaborators

• Seattle Institute for Biomedical and Clinical Research: lead
• United States Department of Defense: collaborator
• VA Puget Sound Health Care System: collaborator

Study Sites (1)

VA Puget Sound Healthcare System

Seattle, Washington, 98108, United States

Location

Related Publications (14)

• Berk E, Black J, Locastro J, Wickis J, Simpson T, Penk W. Traumatogenicity: effects of self-reported noncombat trauma on MMPIs of male Vietnam combat and noncombat veterans treated for substance abuse. J Clin Psychol. 1989 Sep;45(5):704-8. doi: 10.1002/1097-4679(198909)45:53.0.co;2-6.

  PMID: 2808725 BACKGROUND

• Simpson TL, Westerberg VS, Little LM, Trujillo M. Screening for childhood physical and sexual abuse among outpatient substance abusers. J Subst Abuse Treat. 1994 Jul-Aug;11(4):347-58. doi: 10.1016/0740-5472(94)90045-0.

  PMID: 7966505 BACKGROUND

• McCann BS, Simpson TL, Ries R, Roy-Byrne P. Reliability and validity of screening instruments for drug and alcohol abuse in adults seeking evaluation for attention-deficit/hyperactivity disorder. Am J Addict. 2000 Winter;9(1):1-9. doi: 10.1080/10550490050172173.

  PMID: 10914288 BACKGROUND

• Simpson TL. Women's treatment utilization and its relationship to childhood sexual abuse history and lifetime PTSD. Subst Abus. 2002 Mar;23(1):17-30. doi: 10.1080/08897070209511472.

  PMID: 12444358 BACKGROUND

• Simpson TL, Miller WR. Concomitance between childhood sexual and physical abuse and substance use problems. A review. Clin Psychol Rev. 2002 Feb;22(1):27-77. doi: 10.1016/s0272-7358(00)00088-x.

  PMID: 11793578 BACKGROUND

• Simpson TL. Childhood sexual abuse, PTSD, and the functional roles of alcohol use among women drinkers. Subst Use Misuse. 2003 Jan;38(2):249-70. doi: 10.1081/ja-120017248.

  PMID: 12625430 BACKGROUND

• Comtois KA, Tisdall WA, Holdcraft LC, Simpson T. Dual diagnosis: impact of family history. Am J Addict. 2005 May-Jun;14(3):291-9. doi: 10.1080/10550490590949479.

  PMID: 16019979 BACKGROUND

• Simpson TL, Kivlahan DR, Bush KR, McFall ME. Telephone self-monitoring among alcohol use disorder patients in early recovery: a randomized study of feasibility and measurement reactivity. Drug Alcohol Depend. 2005 Aug 1;79(2):241-50. doi: 10.1016/j.drugalcdep.2005.02.001. Epub 2005 Feb 25.

  PMID: 16002033 BACKGROUND

• Dobie DJ, Maynard C, Kivlahan DR, Johnson KM, Simpson T, David AC, Bradley K. Posttraumatic stress disorder screening status is associated with increased VA medical and surgical utilization in women. J Gen Intern Med. 2006 Mar;21 Suppl 3(Suppl 3):S58-64. doi: 10.1111/j.1525-1497.2006.00376.x.

  PMID: 16637948 BACKGROUND

• Bowen S, Witkiewitz K, Dillworth TM, Chawla N, Simpson TL, Ostafin BD, Larimer ME, Blume AW, Parks GA, Marlatt GA. Mindfulness meditation and substance use in an incarcerated population. Psychol Addict Behav. 2006 Sep;20(3):343-7. doi: 10.1037/0893-164X.20.3.343.

  PMID: 16938074 BACKGROUND

• Kaysen D, Simpson T, Dillworth T, Larimer ME, Gutner C, Resick PA. Alcohol problems and posttraumatic stress disorder in female crime victims. J Trauma Stress. 2006 Jun;19(3):399-403. doi: 10.1002/jts.20122.

  PMID: 16788998 BACKGROUND

• Simpson T, Jakupcak M, Luterek JA. Fear and avoidance of internal experiences among patients with substance use disorders and PTSD: the centrality of anxiety sensitivity. J Trauma Stress. 2006 Aug;19(4):481-91. doi: 10.1002/jts.20128.

  PMID: 16929503 BACKGROUND

• Simpson TL, Kaysen D, Bowen S, MacPherson LM, Chawla N, Blume A, Marlatt GA, Larimer M. PTSD symptoms, substance use, and vipassana meditation among incarcerated individuals. J Trauma Stress. 2007 Jun;20(3):239-49. doi: 10.1002/jts.20209.

  PMID: 17597132 BACKGROUND

• Kaysen D, Dillworth TM, Simpson T, Waldrop A, Larimer ME, Resick PA. Domestic violence and alcohol use: trauma-related symptoms and motives for drinking. Addict Behav. 2007 Jun;32(6):1272-83. doi: 10.1016/j.addbeh.2006.09.007. Epub 2006 Nov 13.

  PMID: 17098370 BACKGROUND

MeSH Terms

Conditions

Alcoholism; Stress Disorders, Post-Traumatic; Alcohol Drinking; Drinking Behavior; Substance-Related Disorders; Behavior, Addictive

Interventions

Prazosin; Naltrexone

Condition Hierarchy (Ancestors)

Alcohol-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Behavior; Compulsive Behavior; Impulsive Behavior

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Naloxone; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Results Point of Contact

• Title: Tracy Simpson, PhD
• Organization: Veterans Affairs Puget Sound Health Care System

tracy.simpson@va.gov

206-277-3337

Study Officials

• Tracy Simpson, Ph.D.

  VA Puget Sound Health Care System

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: No study staff, including the participants, will know which condition the participants are in. Only the Research Pharmacist will know the participants' conditions.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Eligible participants will be randomized into one of four study conditions: Naltrexone/Prazosin (Nal/Praz), Naltrexone/Placebo (Nal/Pl), Prazosin/Placebo (Praz/Pl), and Placebo/Placebo (Pl/Pl). Randomization will be blocked by gender, PTSD status, and alcohol consumption goal (abstention vs. reduction) and will be conducted by a VA Puget Sound Research Pharmacist using randomization tables supplied by the study Principal Investigator (PI). The Research Pharmacist will have no additional contacts with the participants.

Study Record Dates

• First Submitted: December 17, 2014
• First Posted: December 22, 2014
• Study Start: March 3, 2015
• Primary Completion: October 10, 2018
• Study Completion: October 10, 2018
• Last Updated: December 29, 2020
• Results First Posted: December 29, 2020

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)