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CAP: Doxazosin in the Treatment of Co-Occurring PTSD and Alcohol Use Disorders (Doxazosin)

Primary Purpose

Posttraumatic Stress Disorder, Alcohol Use Disorders

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

doxazosin

placebo

About this trial

This is an interventional treatment trial for Posttraumatic Stress Disorder focused on measuring PTSD, alcohol use disorders, posttraumatic stress disorder, AUD, Veteran, substance use disorders, SUD

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male or female; any race or ethnicity.
Served in U.S. Military - any branch or operation.
Subjects must be able to comprehend English.
Meet criteria for current (i.e., last 6 months) Substance Use Disorder (SUD) using a modified version of the MINI 7.0 (i.e., must meet DSM-5 criteria for SUD in the past 6 months instead of 12 months).
Meet DSM-5 criteria for current (i.e., last month) PTSD.
Subjects taking psychotropic medications will be required to be maintained on a stable dose for at least four weeks before treatment initiation. This is because initiation or change of medications during the course of the trial may interfere with interpretation of results.
Must consent to random assignment to doxazosin or placebo.
Must consent to complete all treatment and follow-up visits.

Exclusion Criteria:

Subjects meeting DSM-5 criteria for current bipolar affective disorders, as the study protocol may be therapeutically insufficient.
Subjects experiencing significant withdrawal symptoms, as evidence by a score of 10 or above on the Clinical Institute Withdrawal Assessment of Alcohol (CIWA). These subject will be referred for clinical detoxification and may be re-assessed for study eligibility after medically supervised detoxification has been completed.
Individuals considered an immediate suicide risk or who are likely to require hospitalization during the course of the study.
Previous treatment with doxazosin.
Subjects on maintenance anxiolytic, antidepressant, or mood stabilizing medications which have been initiated during the past four weeks. If it is determined, based on clinical criteria, that a subject needs to be started on maintenance medications for anxiety, mood or psychotic symptoms during the course of the study, they may be discontinued from the treatment trial.
Women who are pregnant, nursing or not practicing an effective form of birth control.
Individuals with a history of or current medical illness including unstable angina, myocardial infarction, congestive heart failure or other cardiac condition, hypotension, renal or hepatic disorders, endocrine disorders, prostate or other cancer, pancreatitis, or a seizure disorder.
Subjects with abnormal liver function test (LFTs) as evidenced by laboratory findings of SGOT or SGPT greater than two times normal.
Subjects with a history of adverse reactions to quinazolines or other alpha-1-antagonists (such as allergic reactions, priapism, hepatitis, angioedema, or intraoperative floppy iris syndrome).
Individuals currently taking alpha blockers (terazosin, prazosin), hypnotics/benzodiazepines, atypical antipsychotics (olanzapine, quetiapine, risperidone, clozapine), alpha-2-agonists (Clonidine, methyldopa, tizanidine, guanfacine), conivaptan, boceprevir, idelalisib, PDE-5 inhibitors or alpha-1-antagonists, protease inhibitors (treatment of HIV), oral antifungals, alfuzosin, pazopanib, silodosin, tadalafil, or tamulosin.
MRI exclusions: Claustrophobia; tattoos above the shoulders after evaluation by MRI technician; permanent eyeliner or permanent artificial eyebrows; cardiac pacemaker; metal fragments in eye, skin, or body, including shrapnel; heart valve replacement; brain clips; venous umbrella; being a sheet-metal worker or welder; lifetime history of aneurysm surgery; intracranial bypass, renal, or aortic clips; prosthetic devices such as middle ear, eye, joint, or penile implants; joint replacements; non-removable hearing aid, neurostimulator, or insulin pump; shunts/stents; metal mesh/coil implants; metal plate/pin/screws/wires; or any other metal implants.

Sites / Locations

Ralph H. Johnson VA Medical Center, Charleston, SC

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Doxazosin

Placebo

Arm Description

Participants randomly assigned to receive doxazosin (target dose of 16 mg/day). Doxazosin will be initiated at 1 mg/day for the first week, 2mg/day for the second week, 4mg/day for the third week, 8mg/day for the fourth week, and then increase to 16 mg/day for the remaining eight weeks (as tolerated). Research staff administered the study medication at the weekly visits, and participants were given take-home doses of the medication to self-administer on the days in between study visits.

Participants randomly assigned to placebo. Research staff administered the study medication at the weekly visits, and participants were given take-home doses of the medication to self-administer on the days in between study visits.

Outcomes

Primary Outcome Measures

Clinician Administered PTSD Scale

The primary PTSD outcome measure was the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5; Weathers et al., 2013). The CAPS-5 is a semi-structured interview that measures the DSM-5 symptoms of PTSD and requires the presence of at least one intrusion symptom, one avoidance symptom, two cognition and mood symptoms, and two arousal symptoms for a period of 1 month or more to reach diagnostic threshold. There are 20 symptom items and responses that are rated on a 5-point scale ranging from 0 (absent) to 4 (extreme/incapacitating), with a total PTSD symptom severity score of the sum of the 20 symptom items ranging from 0-80, and lower scores indicating better outcomes (or less severe PTSD symptomology). The CAPS-5 was assessed at end of treatment (week 12).

PTSD Checklist (PCL-5)

The secondary PTSD outcome measure was the PTSD Checklist-5 (PCL-5; Weathers et al., 2013b). The PCL-5 is 20-item self-report measure that assesses the DSM-5 symptoms of PTSD using a severity rating Likert scale ranging from 0 to 4 that indicates the degree of distress across symptoms (0 = not at all to 4 = extremely). The overall score range is 0-80 (and combines the score for all 20 symptoms), with lower scores representing better outcomes (less severe PTSD symptomology). The PCL-5 was assessed at end of treatment (week 12).

Time Line Follow Back (TLFB)

The TLFB obtains retrospective self-report of substance use by using a calendar and memory prompts to stimulate recall (Sobell & Sobell, 1992). Quantity and frequency assessments are made using this instrument (e.g., total number of standard drink units, percent of days using) as well as abstinence (yes/no). TLFB yields consistently high test-retest correlations and correlates well with other self-reports and collateral reports (Sobell et al., 2003). The TLFB assesses frequency and amount of substance use over a pre-determined timeframe. TLFB data were collected throughout the trial, and the values reported here represent the TLFB data at end of treatment (week 12).

Secondary Outcome Measures

Full Information

NCT ID

NCT02500602

First Posted

July 7, 2015

Last Updated

April 16, 2021

Sponsor

VA Office of Research and Development

Collaborators

Medical University of South Carolina

1. Study Identification

Unique Protocol Identification Number

NCT02500602

Brief Title

CAP: Doxazosin in the Treatment of Co-Occurring PTSD and Alcohol Use Disorders

Acronym

Doxazosin

Official Title

CAP - Doxazosin in the Treatment of Co-Occurring PTSD and Alcohol Use Disorders

Study Type

Interventional

2. Study Status

Record Verification Date

April 2021

Overall Recruitment Status

Completed

Study Start Date

June 1, 2016 (Actual)

Primary Completion Date

December 16, 2019 (Actual)

Study Completion Date

December 16, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

VA Office of Research and Development

Collaborators

Medical University of South Carolina

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The proposed study will examine the efficacy of doxazosin in the treatment of PTSD and alcohol use disorder or substance use disorders.

Detailed Description

Due to sustained military conflicts in Afghanistan and Iraq over the past decade, there are an increasing number of U.S. military personnel and Veterans returning home with posttraumatic stress disorder (PTSD) and comorbid alcohol use disorders (AUD) and substance use disorders (SUD). If left untreated, Veterans with co-occurring PTSD and substance use disorders are at increased risk for developing other mental health problems (e.g., depression, anxiety), suicidal ideation and attempts, physical health problems, reduced resiliency and military readiness, employment problems, violence, and family/relationship impairment. While mental health services are in place for U.S. service members, substantial gaps in the treatment of co-occurring PTSD and SUD exist and there is little scientific evidence available to guide the provision of care. As part of the Consortium to Alleviate PTSD (CAP), the proposed study directly addresses this critical knowledge gap by testing the efficacy of doxazosin, a long-acting and selective alpha-1 adrenergic antagonist, as compared to placebo in reducing PTSD and AUD/SUD severity among U.S. military personnel. The medication to be investigated (doxazosin) represents a novel treatment approach for PTSD and AUD/SUD. While prazosin, also an alpha-1 adrenergic antagonist, has been shown to improve sleep and nightmares in military personnel with PTSD and may help reduce substance use severity, it has a short half-life of 2-3 hours and requires multiple doses each day, which is a significant limitation. In several pilot studies, doxazosin has shown promise in significantly reducing symptoms of PTSD and AUD/SUD and, in contrast to prazosin, it requires once per day dosing which confers a significant advantage in terms of translating positive findings into routine clinical practice. In this Stage II study, the investigators will (1) employ a two-arm randomized, double-blind, between-groups experimental design that will consist of 12 weeks of treatment with doxazosin or placebo medication; (2) use standardized, repeated dependent measures to rigorously assess PTSD symptomatology and AUD/SUD severity; (3) measure impairment in associated mental and behavioral health problems (e.g., depression, anxiety, sleep, risky behaviors, family/social functioning); and (4) use functional magnetic resonance imaging (fMRI) to investigate the underlying pathophysiology of comorbid PTSD/AUD and identify prognostic indicators of treatment outcome. To achieve these aims, the investigators have assembled a multidisciplinary team of investigators with nationally-recognized expertise in combat-related PTSD, substance use disorders and neuroimaging who have successfully collaborated in the past and are uniquely qualified to implement this type of investigation. The investigators represent a collaboration of faculty at the Ralph H. Johnson Veterans Affairs (VA) Medical Center and the Medical University of South Carolina (MUSC) in Charleston, SC.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Posttraumatic Stress Disorder, Alcohol Use Disorders

Keywords

PTSD, alcohol use disorders, posttraumatic stress disorder, AUD, Veteran, substance use disorders, SUD

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

144 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Doxazosin

Arm Type

Experimental

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

doxazosin

Intervention Description

active medication

Intervention Type

Drug

Intervention Name(s)

placebo

Intervention Description

placebo pill

Primary Outcome Measure Information:

Title

Clinician Administered PTSD Scale

Description

Time Frame

12 Weeks

Title

PTSD Checklist (PCL-5)

Description

Time Frame

12 Weeks

Title

Time Line Follow Back (TLFB)

Description

Time Frame

12 Weeks

10. Eligibility

Sex

All

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male or female; any race or ethnicity. Served in U.S. Military - any branch or operation. Subjects must be able to comprehend English. Meet criteria for current (i.e., last 6 months) Substance Use Disorder (SUD) using a modified version of the MINI 7.0 (i.e., must meet DSM-5 criteria for SUD in the past 6 months instead of 12 months). Meet DSM-5 criteria for current (i.e., last month) PTSD. Subjects taking psychotropic medications will be required to be maintained on a stable dose for at least four weeks before treatment initiation. This is because initiation or change of medications during the course of the trial may interfere with interpretation of results. Must consent to random assignment to doxazosin or placebo. Must consent to complete all treatment and follow-up visits. Exclusion Criteria: Subjects meeting DSM-5 criteria for current bipolar affective disorders, as the study protocol may be therapeutically insufficient. Subjects experiencing significant withdrawal symptoms, as evidence by a score of 10 or above on the Clinical Institute Withdrawal Assessment of Alcohol (CIWA). These subject will be referred for clinical detoxification and may be re-assessed for study eligibility after medically supervised detoxification has been completed. Individuals considered an immediate suicide risk or who are likely to require hospitalization during the course of the study. Previous treatment with doxazosin. Subjects on maintenance anxiolytic, antidepressant, or mood stabilizing medications which have been initiated during the past four weeks. If it is determined, based on clinical criteria, that a subject needs to be started on maintenance medications for anxiety, mood or psychotic symptoms during the course of the study, they may be discontinued from the treatment trial. Women who are pregnant, nursing or not practicing an effective form of birth control. Individuals with a history of or current medical illness including unstable angina, myocardial infarction, congestive heart failure or other cardiac condition, hypotension, renal or hepatic disorders, endocrine disorders, prostate or other cancer, pancreatitis, or a seizure disorder. Subjects with abnormal liver function test (LFTs) as evidenced by laboratory findings of SGOT or SGPT greater than two times normal. Subjects with a history of adverse reactions to quinazolines or other alpha-1-antagonists (such as allergic reactions, priapism, hepatitis, angioedema, or intraoperative floppy iris syndrome). Individuals currently taking alpha blockers (terazosin, prazosin), hypnotics/benzodiazepines, atypical antipsychotics (olanzapine, quetiapine, risperidone, clozapine), alpha-2-agonists (Clonidine, methyldopa, tizanidine, guanfacine), conivaptan, boceprevir, idelalisib, PDE-5 inhibitors or alpha-1-antagonists, protease inhibitors (treatment of HIV), oral antifungals, alfuzosin, pazopanib, silodosin, tadalafil, or tamulosin. MRI exclusions: Claustrophobia; tattoos above the shoulders after evaluation by MRI technician; permanent eyeliner or permanent artificial eyebrows; cardiac pacemaker; metal fragments in eye, skin, or body, including shrapnel; heart valve replacement; brain clips; venous umbrella; being a sheet-metal worker or welder; lifetime history of aneurysm surgery; intracranial bypass, renal, or aortic clips; prosthetic devices such as middle ear, eye, joint, or penile implants; joint replacements; non-removable hearing aid, neurostimulator, or insulin pump; shunts/stents; metal mesh/coil implants; metal plate/pin/screws/wires; or any other metal implants.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Sudie E. Back, PhD

Organizational Affiliation

Ralph H. Johnson VA Medical Center, Charleston, SC

Official's Role

Principal Investigator

Facility Information:

Facility Name

Ralph H. Johnson VA Medical Center, Charleston, SC

City

Charleston

State/Province

South Carolina

ZIP/Postal Code

29401-5799

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Data Sharing Plan: The data collected from study participants, including PHI, will be entered into and securely stored in the STRONG STAR-CAP database on a secure UTHSCSA server by a member of the study research team under a signed Data Use Agreement between Ralph H. Johnson VA and UTHSCSA. Terms of the Data Use Agreement data have been reviewed and approved by VACO and found to meet VA security compliance standards. Electronic data will be stored, managed, and analyzed by the Data Management and Biostatistics Core staff of the STRONG STAR-CAP Consortium. The overall study PI and named collaborators will have access to identifiable data through the STRONG STAR-CAP website and UTHSCSA server.

Learn more about this trial

CAP: Doxazosin in the Treatment of Co-Occurring PTSD and Alcohol Use Disorders

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