DoD-NAC: NAC for Treating Comorbid PTSD and SUD

• Sponsor: Medical University of South Carolina (Other)
• Overall Status: Completed
• CT.gov ID: NCT02911285
• Collaborator: United States Department of Defense (U.S. Fed), Institute for Translational Neuroscience (Other)
• Enrollment: 90
• Locations: 2
• Arms: 2
• Actual Duration (Months): 37.1
• Patients Per Site: 45
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

As a result of sustained operations in Afghanistan and Iraq, there are an increasing number of U.S. military Veterans with substance use disorders and comorbid posttraumatic stress disorder (PTSD). If left untreated, individuals with substance use disorders and PTSD are at increased risk for developing other mental health problems (e.g., depression, anxiety), suicidal ideation and attempts, medical problems, reduced resiliency and military readiness, vocational problems, and family/social impairment. This study will determine the benefits of N-acetylcysteine (NAC) in treating alcohol use disorder and comorbid post-traumatic stress disorder (PTSD) among military Veterans.

Condition or Disease	Intervention/Treatment	Phase
Posttraumatic Stress Disorder (PTSD); Alcohol Use Disorder (AUD); Substance Use Disorder (SUD)	Drug: N-acetylcysteine; Drug: Placebo; Behavioral: Cognitive behavioral therapy	Phase 2

Detailed Description

As a result of sustained operations in Afghanistan and Iraq, there are an increasing number of U.S. military Veterans with substance use disorders and comorbid posttraumatic stress disorder (PTSD). While mental health services are in place for U.S. service members, substantial gaps in the treatment of co-occurring substance use disorders and PTSD exist and there is little scientific evidence available to guide the provision of care. Treatment for comorbid substance use disorders and PTSD, especially pharmacologic treatment, is largely ineffective and short-lived. While there have been numerous studies focused largely on dopaminergic mechanisms of reward, they have not led to the development of adequate treatments for comorbid substance use disorders and PTSD. Animal models demonstrate that (a) acute stress and chronic use of addictive substances reduce the capacity of glia to remove the neurotransmitter glutamate, and (b) this impairment as well as relapse can be prevented or reversed by N-acetylcysteine (NAC). Further, human studies indicate that NAC is associated with reduced craving and substance use. Based on this, the investigators conducted a Proof of Principle (PoP) study which was the first to examine the use of NAC for the treatment of PTSD, with or without comorbid addiction. In this randomized, controlled double-blind pilot study the investigators showed that Veterans with substance use disorders (81.5% alcohol use disorder) and PTSD who were treated with 2400mg NAC for 8 weeks demonstrated significant reduction in PTSD severity and craving. Moreover, reductions in PTSD and substance-related symptomatology were sustained at 1-month follow-up. However, to extend and confirm its clinical utility in the military/Veteran context, it is important to know whether NAC reduces severity of alcohol use disorder (AUD), the most common addiction among Veterans and military service members, and the mechanisms underlying therapeutic response. Based on promising data from the PoP project, the proposed Extend-and-Confirm (EC) study will determine the efficacy of NAC in reducing AUD and comorbid PTSD in Veterans (N=90). Further, new aims include the application of functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy (1H-MRS) to investigate the pathophysiology of AUD/PTSD, as well as prognostic indicators of treatment outcome. These aims extend the Future Plans proposed in the original PoP study and provide an opportunity for collaboration among clinical and preclinical investigators at the Ralph H. Johnson Veterans Affairs (VA) Medical Center and the Medical University of South Carolina (MUSC) to solve this critical health problem in the military context. In the proposed EC study, the investigators will (1) employ a randomized, double-blind, between-groups experimental design that will consist of 8 weeks of treatment with NAC (2400mg) or placebo medication, and follow-up assessment at 1-, 3-, and 6-months post treatment; (2) use standardized, repeated dependent measures to rigorously assess AUD severity and PTSD symptomatology during treatment and follow-up; (3) collect biologic measures of alcohol use; (4) measure impairment in associated areas of functioning (e.g., depression, sleep, suicidality, risky sexual behaviors, family/social functioning); and (5) employ advanced neuroimaging techniques before and after treatment among a subset of enrolled subjects. This proposal is directly responsive to the missions of the Institute for Translational Neuroscience (ITN), and the US Army/Department of Defense (DoD) in that it seeks to accelerate the development of new, medication-based treatments to mitigate the impact of AUD and comorbid psychological conditions, such as PTSD, in the military/Veteran context. The findings of this study will provide critically needed empirical evidence to help inform practice guidelines and better serve the needs of U.S. service members, Veterans and their families.

Study Design

• Study Type: Interventional
• Actual Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Glial Regulators for Treating Comorbid Posttraumatic Stress Disorder and Substance Use Disorders
• Actual Study Start Date: Oct 1, 2016
• Actual Primary Completion Date: Aug 5, 2019
• Actual Study Completion Date: Nov 4, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NAC/CBT Participants will receive N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT) for 8 weeks.	Drug: N-acetylcysteine; 1200mg bid (2400mg/day); Other Names: NAC ; Behavioral: Cognitive behavioral therapy; CBT for AUD/SUD, one hour/once a week; Other Names: CBT
Placebo Comparator: Placebo/CBT Participants will receive placebo pills and CBT for 8 weeks.	Drug: Placebo; Placebo pills bid; Behavioral: Cognitive behavioral therapy; CBT for AUD/SUD, one hour/once a week; Other Names: CBT

Outcome Measures

Primary Outcome Measures

1. Change in Alcohol Use Disorder Severity [From baseline to week 8 of treatment]

   Change in Alcohol Use Disorder Severity as measured by change in average drinking days per week from baseline to week 8. Greater reduction in drinking days indicates better treatment outcomes. Drinking days measured over 1 week periods (7 days). Scale ranges from 0 days to 7 days.

2. Change in Post Traumatic Stress Disorder Severity [From baseline to week 8]

   Change in post traumatic stress disorder severity as measured by Change in Clinician Administered PTSD Scale (CAPS-5) score from baseline to week 8. Greater change/reduction in score indicates better outcomes and greater reduction in PTSD symptomatology. (minimum score of 0 = absent to a maximum score of 80 = extreme)

3. Change in Alcohol Craving [From baseline to week 8]

   Change in Alcohol craving as measured by change in Obsessive Compulsive Drinking Scale (OCDS) Total Score. Greater change/reduction in score indicates better outcomes and reduced alcohol craving. (Scores range from 0 to 56)

4. Change in Post Traumatic Stress Disorder Severity [From baseline to week 8]

   Post traumatic stress disorder symptoms as measured by change/reduction in score of post traumatic stress disorder checklist (PCL-5) from baseline to week 8. Greater reduction in score indicates better treatment outcomes. (minimum score of 0 = absent to a maximum score of 80 = extreme)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female, any race or ethnicity, age 18 to 75 years old.

• U.S. military Veteran, including National Guard and Reservists.

• Able to comprehend English.

• Meet Diagnostic and Statistical Manual (DSM-5) criteria for current alcohol use disorder (AUD) and/or substance use disorder (SUD).

• 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 (e.g., panic disorder, agoraphobia, social phobia, generalized anxiety 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 PTSD (Brady et al., 2000; Kessler et al., 2005).

• 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 N-acetylcysteine (NAC) or placebo.

• Must consent to complete all treatment and follow-up visits.

Exclusion Criteria:

• Subjects meeting DSM-5 criteria for a history of or current psychotic or bipolar affective disorders, as the study protocol may be therapeutically insufficient.

• Subjects with a current eating disorder (bulimia, anorexia nervosa) or with dissociative identity disorder, as they are likely to require specific time-intensive psychotherapy.

• Subjects experiencing significant withdrawal symptoms, as evidence by a score of 10 or above on the Clinical Institute Withdrawal Assessment of Alcohol (CIWA).These subjects 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 based on the Columbia Suicide Severity Rating Scale (C-SSRS) or who are likely to require hospitalization during the course of the study.

• Women who are pregnant, nursing or not practicing an effective form of birth control.

• Asthma or any clinically significant medical condition that in the opinion of the investigators would adversely affect safety or study participation.

• Use of carbamazepine, phenytoin, nitrous oxide, methotrexate, 6 azauridine triacetate, or nitroglycerin within the last 14 days or any other medication felt to have a hazardous interaction if taken with NAC.

• History of childhood or adult seizures of any cause.

• MRI exclusions: Claustrophobia; tattoos above the shoulders; 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. Note that individuals who meet inclusion/exclusion criteria for the medication component of the study but not the MRI portion (e.g., excluded due to metal implants) will still be eligible to enroll in and complete the medication/treatment phase.

• 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 will be discontinued from the treatment trial.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical University of South Carolina	Charleston	South Carolina	United States	29401
2	Ralph H Johnson VA Medical Center	Charleston	South Carolina	United States	29401

Sponsors and Collaborators

• Medical University of South Carolina
• United States Department of Defense
• Institute for Translational Neuroscience

Investigators

• Principal Investigator: Sudie Back, Ph.D., Medical University of South Carolina

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 19, 2019
• Informed Consent Form - Apr 26, 2019

More Information

Publications

None provided.

• Responsible Party: Medical University of South Carolina
• ClinicalTrials.gov Identifier: NCT02911285
• Other Study ID Numbers: Pro00052757
• First Posted: Sep 22, 2016
• Last Update Posted: May 19, 2021
• Last Verified: Apr 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Medical University of South Carolina: Alcohol; PTSD; Trauma; Veteran; Substance; Drug; Post Traumatic Stress Disorder; Military
• Additional relevant MeSH terms: Disease; Substance-Related Disorders; Alcoholism; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Acetylcysteine; N-monoacetylcystine

Study Results

Participant Flow

Arm/Group Title	N-acetylcysteine (NAC) Plus Cognitive Behavioral Therapy (CBT)	Placebo + Cognitive Behavioral Therapy (CBT)
Arm/Group Description	Participants randomized to N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT) for 8 weeks. N-acetylcysteine: 1200mg bid (2400mg/day) Cognitive behavioral therapy: CBT for AUD/SUD, one hour/once a week	Participants received placebo pills and Cognitive Behavioral Therapy (CBT) for 8 weeks. Placebo: Placebo pills bid Cognitive behavioral therapy: CBT for AUD/SUD, one hour/once a week
Period Title: Overall Study
STARTED	49	41
COMPLETED	40	36
NOT COMPLETED	9	5

Baseline Characteristics

Arm/Group Title	N-acetylcysteine + Cognitive Behavioral Therapy	Placebo + Cognitive Behavioral Therapy	Total
Arm/Group Description	Participants received N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT) for 8 weeks. N-acetylcysteine: 1200mg bid (2400mg/day) Cognitive behavioral therapy: CBT for AUD/SUD, one hour/once a week	Participants received placebo pills and CBT for 8 weeks. Placebo: Placebo pills bid Cognitive behavioral therapy: CBT for AUD/SUD, one hour/once a week	Total of all reporting groups
Overall Participants	49	41	90
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	52.99 (11.51)	49.13 (13.23)	50.85 (11.92)
Sex: Female, Male (Count of Participants)
Female	5 10.2%	2 4.9%	7 7.8%
Male	44 89.8%	39 95.1%	83 92.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 6.1%	1 2.4%	4 4.4%
Not Hispanic or Latino	46 93.9%	40 97.6%	86 95.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	26 53.1%	20 48.8%	46 51.1%
White	20 40.8%	21 51.2%	41 45.6%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 6.1%	0 0%	3 3.3%
Region of Enrollment (participants) [Number]
United States	49 100%	41 100%	90 100%

Outcome Measures

1. Primary Outcome

Title	Change in Alcohol Use Disorder Severity
Description	Change in Alcohol Use Disorder Severity as measured by change in average drinking days per week from baseline to week 8. Greater reduction in drinking days indicates better treatment outcomes. Drinking days measured over 1 week periods (7 days). Scale ranges from 0 days to 7 days.
Time Frame	From baseline to week 8 of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT)	Placebo and Cognitive Behavioral Therapy (CBT)
Arm/Group Description	Participants received N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT) for 8 weeks. N-acetylcysteine: 1200mg twice per day (2400mg/day) Cognitive behavioral therapy: for alcohol/substance use disorder, one hour/once a week	Participants received placebo pills and CBT for 8 weeks. Placebo: Placebo pills twice per day Cognitive behavioral therapy: for alcohol/substance use disorder, one hour/once a week
Measure Participants	40	36
Mean (Standard Deviation) [drinking days reduction]	-2.65 (3.85)	-2.82 (4.86)

2. Primary Outcome

Title	Change in Post Traumatic Stress Disorder Severity
Description	Change in post traumatic stress disorder severity as measured by Change in Clinician Administered PTSD Scale (CAPS-5) score from baseline to week 8. Greater change/reduction in score indicates better outcomes and greater reduction in PTSD symptomatology. (minimum score of 0 = absent to a maximum score of 80 = extreme)
Time Frame	From baseline to week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT)	Placebo and Cognitive Behavioral Therapy (CBT)
Arm/Group Description	Participants received N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT) for 8 weeks. N-acetylcysteine: 1200mg bid (2400mg/day) Cognitive behavioral therapy: CBT for AUD/SUD, one hour/once a week	Participants received placebo pills and CBT for 8 weeks. Placebo: Placebo pills bid Cognitive behavioral therapy: CBT for AUD/SUD, one hour/once a week
Measure Participants	40	36
Mean (Standard Deviation) [score on a scale]	-6.93 (13.42)	-5.53 (11.10)

3. Primary Outcome

Title	Change in Alcohol Craving
Description	Change in Alcohol craving as measured by change in Obsessive Compulsive Drinking Scale (OCDS) Total Score. Greater change/reduction in score indicates better outcomes and reduced alcohol craving. (Scores range from 0 to 56)
Time Frame	From baseline to week 8

Outcome Measure Data

Analysis Population Description

39 participants completed survey in NAC group and 37 participants completed survey in placebo group

Arm/Group Title	N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT)	Placebo and Cognitive Behavioral Therapy (CBT)
Arm/Group Description	Participants received N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT) for 8 weeks. N-acetylcysteine: 1200mg bid (2400mg/day) Cognitive behavioral therapy: CBT for AUD/SUD, one hour/once a week	Participants received placebo pills and CBT for 8 weeks. Placebo: Placebo pills bid Cognitive behavioral therapy: CBT for AUD/SUD, one hour/once a week
Measure Participants	39	37
Mean (Standard Deviation) [score on a scale]	-3.97 (7.26)	-2.92 (5.97)

4. Primary Outcome

Title	Change in Post Traumatic Stress Disorder Severity
Description	Post traumatic stress disorder symptoms as measured by change/reduction in score of post traumatic stress disorder checklist (PCL-5) from baseline to week 8. Greater reduction in score indicates better treatment outcomes. (minimum score of 0 = absent to a maximum score of 80 = extreme)
Time Frame	From baseline to week 8

Outcome Measure Data

Analysis Population Description

39 participants completed survey in NAC group, and 37 completed survey in placebo group

Arm/Group Title	N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT)	Placebo and Cognitive Behavioral Therapy (CBT)
Arm/Group Description	Participants received N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT) for 8 weeks. N-acetylcysteine: 1200mg twice per day (2400mg/day) Cognitive behavioral therapy for alcohol/substance use disorder, one hour/once a week	Participants received placebo pills and CBT for 8 weeks. Placebo: Placebo pills twice per day Cognitive behavioral therapy for alcohol/substance use disorder, one hour/once a week
Measure Participants	39	37
Mean (Standard Deviation) [score on a scale]	-12.97 (18.36)	-9.97 (16.75)

Adverse Events

Time Frame	Approximately 8-9 months.
Arm/Group Title	N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT)		Placebo and Cognitive Behavioral Therapy (CBT)
Arm/Group Description	Participants received N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT) for 8 weeks. N-acetylcysteine: 1200mg bid (2400mg/day) Cognitive behavioral therapy: CBT for AUD/SUD, one hour/once a week		Participants received placebo pills and CBT for 8 weeks. Placebo: Placebo pills bid Cognitive behavioral therapy: CBT for AUD/SUD, one hour/once a week
All Cause Mortality
	N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT)		Placebo and Cognitive Behavioral Therapy (CBT)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/49 (0%)		0/41 (0%)
Serious Adverse Events
	N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT)		Placebo and Cognitive Behavioral Therapy (CBT)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/49 (6.1%)		2/41 (4.9%)
Blood and lymphatic system disorders
Severe Nose Bleed	1/49 (2%)	1	0/41 (0%)	0
Cardiac disorders
Congestive Heart Failure	1/49 (2%)	1	0/41 (0%)	0
Hepatobiliary disorders
Liver Lesions	0/49 (0%)	0	1/41 (2.4%)	1
Psychiatric disorders
Suicidal Ideation	0/49 (0%)	0	1/41 (2.4%)	1
Aborted Suicide Attempt	1/49 (2%)	1	0/41 (0%)	0
Other (Not Including Serious) Adverse Events
	N-acetylcysteine (NAC) and Cognitive Behavioral Therapy (CBT)		Placebo and Cognitive Behavioral Therapy (CBT)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/49 (61.2%)		28/41 (68.3%)
Gastrointestinal disorders
Diarrhea	6/49 (12.2%)	6	3/41 (7.3%)	3
Flatulence	5/49 (10.2%)	5	1/41 (2.4%)	1
Nausea	1/49 (2%)	1	3/41 (7.3%)	3
Vomiting	0/49 (0%)	0	3/41 (7.3%)	3
General disorders
Fatigue	5/49 (10.2%)	5	4/41 (9.8%)	4
Metabolism and nutrition disorders
Appetite Changes	1/49 (2%)	1	3/41 (7.3%)	3
Musculoskeletal and connective tissue disorders
Back Pain	3/49 (6.1%)	3	4/41 (9.8%)	4
Knee Pain	1/49 (2%)	1	4/41 (9.8%)	4
Nervous system disorders
Headache	4/49 (8.2%)	4	1/41 (2.4%)	1
Psychiatric disorders
Insomnia	1/49 (2%)	1	3/41 (7.3%)	3
Respiratory, thoracic and mediastinal disorders
Cold	13/49 (26.5%)	13	14/41 (34.1%)	14

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.