A Randomised Controlled Trial of N-acetylcysteine for the Management of Alcohol Use Disorder (NAC-AUD)

To explore the effectiveness of n-acetylcysteine in improving treatment outcomes for alcohol use disorder in a double-blind randomised placebo-controlled trial.

Study Overview

• Status: Recruiting
• Conditions: Alcohol Use Disorder (AUD)
• Intervention / Treatment: Drug: Placebo; Drug: N-acetyl cysteine

Detailed Description

Australia urgently requires new treatment strategies for the treatment of alcohol dependence. Although alcohol use disorders are a leading cause of preventable death in Australia, their treatment is generally not evidence based. The medications currently approved for use in Australia for the management of alcohol dependence have limited efficacy, and existing research does not address the heterogeneity of treatment response. Targeted personalised medicine addresses this heterogeneity with better medicine selection for patients based on their genotype and clinical comorbidities.

Following on from a recent pilot study conducted by CI Morley (NCT03879759), this project will evaluate the clinical efficacy and tolerability of NAC, relative to a placebo, in heavy drinkers. We hypothesise that NAC-treated participants will be better able to achieve a reduction in heavy drinking. We will utilise a double-blind, randomised, controlled design. A sample of 280 individuals will receive 12 weeks of treatment with NAC (2400 mg/day) or placebo.

• Study Type: Interventional
• Enrollment (Anticipated): 280
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2050
      • Recruiting
      • Drug Health Services, Royal Prince Alfred Hospital
      • Contact: Kirsten Morley; Email: Kirsten.morley@sydney.edu.au
      • Principal Investigator: Paul Haber
  • Queensland
    • Annerley, Queensland, Australia, 4103
      • Not yet recruiting
      • Cornwall Street Medical Centre (UQ Health Care)
      • Contact: Paul Clark, MBBS; Email: paul.j.clark@uq.edu.au
      • Principal Investigator: Paul Clark, MBBS
  • Victoria
    • Richmond, Victoria, Australia, 3121
      • Active, not recruiting
      • Turning Point

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Alcohol Use Disorder according to the DSM-V criteria
• A desire to reduce or stop drinking
• Consumed at least 21 standard drinks per week or 2 heavy drinking days per week (HDD: ≥ 5 standard drinks/day for men; ≥4 for women) in the month prior to screening
• Adequate cognition and English language skills to give valid consent and complete research interviews
• Stable housing
• Willingness to give written informed consent

Exclusion Criteria:

• Pregnancy or lactation (women will be advised to use reliable contraception during the trial and a pregnancy test will be performed were necessary)
• Concurrent use of any psychotropic medication other than antidepressants (provided these are taken at stable doses for at least two months)
• Any substance dependence other than nicotine
• Clinically unstable systemic medical (e.g. cancer, end stage liver disease: e.g. MELD score ≥ 10) or psychiatric disorder (e.g. active psychosis, borderline personality disorder, active suicide risk: e.g. MADRAS item 10 score of 6) that precludes trial participation
• Concurrent use of selenium, vitamin D or other anti-oxidants
• Any alcohol pharmacotherapy within the past month

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: N-acetyl Cysteine; Generic name: N-acetyl cysteine. Brand: ACC-600 (Acetylcysteine). Strength: 600mg per capsule. Form: capsule Route: oral Frequency: 2x capsules twice per day = total 4 capsules/day Duration: 12 weeks + Standard of Care: Medical Management.	Drug: N-acetyl cysteine; 2400mg/day; Other Names: NAC
Placebo Comparator: Placebo; Matched placebo Generic name: dicalcium phosphate Strength: 600mg per capsule Form: capsule Route: oral Frequency: 2x capsules twice per day = total 4 capsules/day Duration: 12 weeks. + Standard of Care: Medical Management.	Drug: Placebo; Matched placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Heavy Drinking Days	Reduction in Heavy Drinking Days (HDD; defined as 4 or more drinks in a day for women and five or more drinks in a day for men). This will be measured by the Timeline Follow Back and corroborated with Phosphatidylethanol (PEth) levels	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Liver Function	Liver Function will be assessed through blood sample at baseline. We will measurement levels of enzyme gamma-glutamyl transferase (GGT), aspartate transaminase (AST), and alanine transaminase (ALT).	24 weeks
Absence of any HDD	Measured by Timeline Follow Back and corroborated with Phosphatidylethanol (PEth) levels	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cost-Efficacy	Examine the cost-efficacy between NAC and placebo from both health sector and societal perspectives. Measured by Disability-Adjusted Life Years (DALYs)	12 weeks
Changes in Alcohol Craving	As measured by the Alcohol Craving Experience Questionnaire (ACEQ). Higher scores indicate more severe craving.	24 weeks
Mean alcohol consumption per drinking day	Measured by Timeline Follow Back and corroborated with Phosphatidylethanol (PEth) levels	24 weeks
Change in dependence Severity	Measured by the Alcohol Dependence Scale. The minimum score is 0 and the maximum score is 47. A higher score indicates more severe dependence.	24 weeks
Changes in Anxiety	Measured by cumulative scores on the DASS-21 Anxiety Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates more anxiety.	24 weeks
Changes in Depression	Measured by cumulative scores on the DASS-21 Depression Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates greater depression.	24 weeks
Changes in Stress	Measured by cumulative scores on the DASS-21 Stress Scale. This scale has a minimum score of 0 and maximum score of 21. A higher score indicates more stress.	24 weeks
Sleep Disturbances	As measured by the ISI (Insomnia Severity Index). This Index has a minimum score of 0 and a maximum score of 28. The higher the score indicates more severe insomnia.	24 weeks
Lifetime Consequences related to Drinking	To examine the adverse consequences a participant has experienced in their lifetime due to alcohol abuse in five areas: Interpersonal, Physical, Social, Impulsive, and Intrapersonal. This is measured using the Drinker Inventory of Consequences Lifetime Edition (DrInC-2L). Higher scores indicate more consequences.	Baseline
Recent Consequences related to Drinking	To examine the adverse consequences a participant has experienced in the last 3 months due to alcohol abuse in five areas: Interpersonal, Physical, Social, Impulsive, and Intrapersonal. This is measured using the Drinker Inventory of Consequences Recent Edition (DrInC-2R). Higher scores indicate more consequences.	12 weeks
Changes in Consequences related to Drinking	To examine the change in adverse consequences a participant has experienced across the trial due to alcohol abuse in five areas: Interpersonal, Physical, Social, Impulsive, and Intrapersonal. This is measured by comparing the Drinker Inventory of Consequences Recent Edition (DrInC-2R) and the Drinker Inventory of Consequences Lifetime Edition (DrInC-2L). Higher scores indicate more consequences.	24 weeks
Drinking Dairy	Daily texts will be sent out to participants querying the amount of alcohol they have consumed. Participant responses to this will be recorded. This will be managed through SEMA software.	12 weeks
Nicotine Dependence	Measured by the Fagerstrom Test for Nicotine Dependence (FTND). This test has a minimum score of 0 and a maximum score of 10. Higher scores indicate a more intense physical dependence on nicotine.	Baseline
Changes in Suicidal Ideation	As measured by the Suicidal Ideation Attributes Scale (SIDAS). This scale has a minimum score of 0 and a maximum score of 50. Higher scores indicate more severe suicidal thoughts.	24 weeks
Changes in Information Gathering ability	As measured by the Caravan Spotter task of the Cognitive Impulsivity Suite (CIS). This measures information gathering through a perceptual decision making task whereby the target is initially ambiguous but progressively becomes clearer.	24 weeks
Changes in Attentional Control	As measured by the Bounty Hunter task of the Cognitive Impulsivity Suite (CIS). This measures attentional control using a Go/No Go task.	24 weeks
Changes in Monitoring of Feedback	As measured by the Prospectors Gamble task of the Cognitive Impulsivity Suite (CIS). This involves a probabilistic reverse learning task to measure monitoring of feedback.	24 weeks
Irritability	As measured by the Brief Irritability Test (BITe). This test has a minimum score of 0 and a maximum score of 30. Higher scores indicate greater irritability.	Baseline
Changes in Physical Activity	To assess an individuals' health based on the previous 7 days of physical activity. This is measured by the International Physical Activity Questionnaire (IPAQ-Long). We are interested in whether across treatment, answers to this questionnaire will change.	24 weeks
Changes in Quality of Life	To assess whether treatment can change quality of life as measured by the short form Health Survey (SF-36). This survey has 36 items that measure 8 domains of health, including: physical functioning, physical role limitations, bodily pain, general health perceptions, energy/vitality, social functioning, emotional role limitations and mental health. The scores are transformed to range from 0 (worst possible health) to 100 (best possible health).	24 weeks
Changes in Quality of Life	As measured by the EQ-5D-5L. This instrument measures 5 different domains of life including: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each domain is assessed by one question. This instrument has a minimum score of 0 (worst possible health) and a maximum score of 1 (best possible health).	24 weeks
Changes in ability to inhibit prepotent responses	As measured by the Stroop Colour Word Test. This test measures ability to inhibit prepotent responses and processing speed. This is assessed through the time it takes for an individual to appropriately select an incongruent response. For example, selecting "black" for the word "black" that is coloured in "green". Higher scores indicate worse performance.	24 weeks
Changes in processing speed	As measured by the Trail Making Task (TMT). This test measures the ability to an individual to process visual stimuli, as measured in time. In the TMT Part A, individuals are instructed to draw a line between numbers, 1-2-3-4-5. Higher time indicates slower processing speed. In the TMT Part B individuals are instructed to switch between drawing lines between numbers and letters, for example 1-A-2-B-3-C. Higher time indicates worse processing speed and switching ability.	24 weeks
Changes in DSM-5 PTSD symptomology	As measured by the PCL-5. This self-report questionnaire lists 20-items that assess DSM-5 PTSD criteria. A higher score indicates greater severity	24 weeks
Changes in use of Health Services	As measured by the Brief Health Services Use Questionnaire. This questionnaire assesses Health Service Use across the last 3 months.	24 weeks
Hangover Diary	Daily texts will be sent out to participants querying the hangover symptoms they are experiencing, if any. Participant responses to this will be recorded. This will be managed through SEMA software.	12 weeks
Using Redox Markers to predict treatment response	We will use blood samples collected at baseline to measure redox markers (GPxBC, GSHBC). At the end of treatment we will see whether these markers are predictive of treatment response	Baseline
Changes in Redox Markers	We will use blood samples collected at baseline and wk 12 to measure changes in redox markers (GPxBC, GSHBC)	12 weeks

Collaborators and Investigators

• Sponsor: University of Sydney
• Collaborators: Monash University

Study record dates

Study Major Dates

• Study Start (Actual): February 16, 2023
• Primary Completion (Anticipated): November 1, 2025
• Study Completion (Anticipated): November 1, 2026

Study Registration Dates

• First Submitted: June 2, 2022
• First Submitted That Met QC Criteria: June 2, 2022
• First Posted (Actual): June 7, 2022

Study Record Updates

• Last Update Posted (Actual): March 16, 2023
• Last Update Submitted That Met QC Criteria: March 14, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Alcohol Dependence; N-acetylcysteine; NAC; N-acetyl Cysteine
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Drinking Behavior; Alcohol-Related Disorders; Substance-Related Disorders; Alcohol Drinking; Alcoholism; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: X21-0342

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No