Clinical Trial for Alcohol Use Disorder and Post Traumatic Stress Disorder (PTSD)

A Randomized Controlled Trial of N-Acetylcysteine for Alcohol Use Disorder and Comorbid Post Traumatic Stress Disorder

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02966873

Enrollment

182

Registered

2016-11-17

Start date

2016-10-01

Completion date

2022-09-19

Last updated

2025-02-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Post Traumatic Stress Disorder (PTSD), Addiction, Alcohol Abuse

Keywords

Post Traumatic Stress Disorder (PTSD), Addiction, Alcohol Use Disorder, Cognitive Behavioral Therapy, N-acetylcysteine (NAC)

Brief summary

This is a randomized controlled Phase II clinical trial designed to evaluate the effects of N-acetylcysteine (NAC) in reducing Alcohol Use Disorder (AUD) severity and Post Traumatic Stress Disorder (PTSD) symptomatology among individuals with current AUD and PTSD.

Detailed description

The primary objective of the proposed Phase II study is to evaluate the effects of N-acetylcysteine (NAC), in reducing (1) Alcohol Use Disorder (AUD) severity and (2) Post Traumatic Stress Disorder (PTSD) symptomatology among individuals (N=200) with current AUD and PTSD. We will also use functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (MRS) to investigate the neural circuitry and neurochemistry underlying comorbid AUD/PTSD and prognostic indicators of positive treatment response. Secondary objectives are to evaluate the effects of NAC on impairment in associated areas of functioning (e.g., depression, anxiety, sleep, risky behaviors). In order to accomplish this we will (1) employ an intent-to-treat, double-blind, placebo-controlled randomized controlled trial that will consist of 12 weeks of treatment with NAC (2400 mg per day) or placebo medication; (2) examine standardized, repeated dependent measures of clinical outcomes at baseline, week 6, week 12, and 3-, 6-, and 12-month follow-up; and (3) employ advanced neuroimaging methodologies, a laboratory cue paradigm, and collect biologic measures of alcohol consumption. All participants will also undergo weekly individual cognitive behavior therapy sessions (CBT).The following specific aims are proposed: Specific Aim 1: To determine the efficacy of N-acetylcysteine (NAC), as compared to placebo, in reducing alcohol use severity (i.e., total standard drinks, percent days drinking, abstinence rates) and craving. Specific Aim 2: To determine the efficacy of N-acetylcysteine (NAC), as compared to placebo, in reducing self-report and clinician-rated PTSD symptomatology. Specific Aim 3: To use multimodal neuroimaging techniques to investigate the pathophysiology underlying AUD and comorbid PTSD, and prognostic indicators of treatment outcome. The proposed study will answer critical questions regarding the potential of NAC as an effective pharmacotherapy for AUD and comorbid PTSD, and elucidate possible mechanisms underlying improved outcomes. This study has the particular advantage of building directly on positive preliminary findings by (1) further testing NAC in the treatment of individuals with co-occurring AUD/PTSD using a double-blind, placebo-controlled randomized design; (2) measuring functioning in related areas, such as depression and risky behaviors; (3) employing innovative measurements including neuroimaging and laboratory cue paradigms; and (4) employing a multidisciplinary team of experts who have successfully collaborated in the past and are uniquely qualified to implement this type of investigation. This project is directly responsive to the mission of the National Institute of Alcohol and Alcoholism (NIAAA) and the new AUD/PTSD initiative in that it seeks to evaluate a promising therapeutic agent for the treatment of AUD/PTSD and identify neurobiological mechanisms common to AUD/PTSD as potential treatment targets. The findings from this study have the potential to significantly improve the standard of patient care, advance the comorbidity science in this area, and decrease public health expenditures associated with AUD and comorbid PTSD.

Interventions

DRUGN-Acetylcysteine (NAC) Treatment

Participant will receive 12 weeks of Active Treatment NAC (2400 mg) daily. The study medication will be provided in blister packs in the form of 600 mg tablets. Each participant will be asked to take two (2) 600 mg tablets in the morning and two (2) 600 mg tablets in the evening.

BEHAVIORALCognitive Behavioral Therapy (CBT)

Participant will receive 12 weeks of weekly cognitive-behavioral therapy, medication management, and AE monitoring.

DRUGInactive Placebo Oral Capsule

Participant will receive 12 weeks of inactive placebo. The study medication will be provided in blister packs in the form of 600 mg tablets. Each participant will be asked to take two (2) 600 mg tablets in the morning and two (2) 600 mg tablets in the evening.

OTHERFunctional magnetic resonance imaging (fMRI)

Participants will be given the option to complete Functional magnetic resonance imaging (fMRI) at two timepoints (pre-treatment and end of treatment).

OTHERProton magnetic resonance spectroscopy (MRS) Imaging

Participants will be given the option to complete magnetic resonance spectroscopy (MRS) at two timepoints (pre-treatment and end of treatment).

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Yes

Inclusion criteria

1. Male or female; any race or ethnicity; age 18 to 70 years old. 2. Subjects must be able to comprehend English. 3. Meet DSM-5 criteria for current alcohol use disorder (AUD). 4. Meet DSM-5 criteria for current PTSD or subthreshold PTSD. Subjects may also meet criteria for a mood disorder (except bipolar affective disorder, see

Exclusion criteria

) or other anxiety disorders (panic disorder, agoraphobia, social phobia, generalized anxiety disorder, or obsessive compulsive disorder). The inclusion of subjects with affective and other anxiety disorders is essential because of the marked frequency of the co-existence of mood and other anxiety disorders among patients with AUD and PTSD (Brady et al., 2000; Kessler et al., 2005). Subjects may meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for another substance use disorder as long as AUD is the primary substance of choice. 5. 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. 6. Must consent to random assignment to N-acetylcysteine (NAC) or placebo. 7. Must consent to complete all treatment and follow-up visits.

Design outcomes

Primary

Measure	Time frame	Description
Change in Alcohol Use Severity	From baseline to week 12	Change in Alcohol Use Severity as measured by standard drinks per day using the Time Line Follow Back (TLFB) to measure alcohol consumption. Fewer standard drinks per day represent better outcomes. Greater change in standard drinks per day represents better outcomes.
Change in Alcohol Craving - Obsessive Subscale	From baseline to week 12	Change in Alcohol Craving as measured by the Obsessive Compulsive Drinking Scale (OCDS) to measure the obsessive subscale of alcohol craving. The OCDS is a 14-item questionnaire that measures alcohol use and attempts to control drinking. Obsessive subscale includes items 1-6. Each item is scored on a scale from 0 to 4. Scores range from 0 to 28, with lower scores representing better outcomes.
Change in Post Traumatic Stress Disorder Symptom Severity - Clinician Rated	From baseline to week 12	Change in Post Traumatic Stress Disorder symptom severity as measured by Clinician Administered PTSD Scale (CAPS-5) for clinician-rated posttraumatic stress symptoms. The CAPS-5 is a 30-item structured interview. CAPS-5 total symptom severity score is calculated by summing severity scores for the 20 PTSD symptoms, each with severity scores ranging from 0-4. The overall total severity score for CAPS-5 ranges from 0-80, with lower scores representing better outcomes (less severe PTSD).
Change in Post Traumatic Stress Disorder Symptom Severity - Self Report	From baseline to week 12	Change in Post Traumatic Stress Disorder (PTSD) symptom severity as measured by the Posttraumatic Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition \[DSM-5\](PCL-5) for self-reported symptoms. The PCL-5 is a 20-item self-report measure that assesses the 20 symptoms of PTSD. The rating scale is 0-4 for each symptom/item, and overall scores range from 0-80, with lower scores representing better outcomes (less severe PTSD).
Change in Alcohol Craving - Compulsive Subscale	From baseline to week 12	Change in Alcohol Craving as measured by the Obsessive Compulsive Drinking Scale (OCDS) to measure the compulsive subscale of alcohol craving. The OCDS is a 14-item questionnaire that measures alcohol use and attempts to control drinking. Compulsive subscale includes items 7-14. Each item is scored on a scale from 0 to 4. Scores range from 0 to 32, with lower scores representing better outcomes.
Change in Alcohol Use Severity - Percent Days Abstinent	From baseline to week 12	Change in Alcohol Use Severity as measured by the percent days abstinent using the Time Line Follow Back (TLFB) to measure alcohol consumption. Greater percentage of days of abstinence represents better outcomes. Greater change in Percent Days Abstinent represents better outcomes.

Countries

United States

Participant flow

Recruitment details

Recruitment for this project was ongoing from June 2016 through June 2021. Prior to the Coronavirus pandemic, recruitment efforts were focused in Charleston, South Carolina (clinics, online, community). In 2020, the study team shifted to a full remote approach and opened recruitment across the continental United States.

Pre-assignment details

Participants were stratified by alcohol use disorder severity and posttraumatic stress disorder severity. Stratified random block randomization was used to balance the randomization assignment with respect to these strata. The purpose of stratification is to distribute these potential prognostic factors equally across treatment groups.

Participants by arm

Arm	Count
N-Acetylcysteine (NAC) Treatment Group Participant will receive 12 weeks of Active Treatment NAC (2400 milligrams \[mg\]) daily, as well as weekly cognitive-behavioral therapy, medication management, and Adverse Event (AE) monitoring. The study medication provided in blister packs in the form of 600 mg tablets. Each participant will be asked to take two (2) 600 mg tablets in the morning and two (2) 600 mg tablets in the evening. Cognitive Behavioral Therapy (CBT): All participant will receive 12 weeks of weekly cognitive-behavioral therapy, medication management, and AE monitoring.	93
Placebo Group Participants receive 12 weeks of inactive placebo comparator daily, as well as weekly cognitive-behavioral therapy, medication management, and Adverse Event (AE) monitoring. The study medication (placebo) provided in blister packs in the form of 600 milligrams \[mg\] tablets. Each participant will be asked to take two (2) 600 mg tablets in the morning and two (2) 600 mg tablets in the evening. Cognitive Behavioral Therapy (CBT): All participant will receive 12 weeks of weekly cognitive-behavioral therapy, medication management, and AE monitoring.	89
Total	182

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Lost to Follow-up	16	15

Baseline characteristics

Characteristic	N-Acetylcysteine (NAC) Treatment Group	Placebo Group	Total
Age, Continuous	40.9 years STANDARD_DEVIATION 13.2	39.7 years STANDARD_DEVIATION 12.4	40.3 years STANDARD_DEVIATION 12.8
Race/Ethnicity, Customized Ethnicity, % Hispanic	4 Participants	4 Participants	8 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Asian	4 Participants	0 Participants	4 Participants
Race (NIH/OMB) Black or African American	14 Participants	18 Participants	32 Participants
Race (NIH/OMB) More than one race	2 Participants	4 Participants	6 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	72 Participants	66 Participants	138 Participants
Sex: Female, Male Female	57 Participants	56 Participants	113 Participants
Sex: Female, Male Male	36 Participants	33 Participants	69 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 93	1 / 89
other Total, other adverse events	39 / 93	39 / 89
serious Total, serious adverse events	5 / 93	3 / 89

Outcome results

Primary

Change in Alcohol Craving - Compulsive Subscale

Change in Alcohol Craving as measured by the Obsessive Compulsive Drinking Scale (OCDS) to measure the compulsive subscale of alcohol craving. The OCDS is a 14-item questionnaire that measures alcohol use and attempts to control drinking. Compulsive subscale includes items 7-14. Each item is scored on a scale from 0 to 4. Scores range from 0 to 32, with lower scores representing better outcomes.