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Trial registered on ANZCTR


Registration number
ACTRN12618000366257
Ethics application status
Approved
Date submitted
2/03/2018
Date registered
9/03/2018
Date last updated
14/01/2024
Date data sharing statement initially provided
20/12/2018
Date results information initially provided
7/01/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
The N-ICE Trial: A trial of N-Acetyl-Cysteine (NAC) for methamphetamine dependence
Scientific title
The N-ICE Trial: A randomised double-blind placebo-controlled study of the safety and efficacy of N-Acetyl-Cysteine (NAC) as a pharmacotherapy for methamphetamine (“ice”) dependence
Secondary ID [1] 294206 0
Curtin University Protocol Number: N-ICE Trial
Universal Trial Number (UTN)
U1111-1210-1224
Trial acronym
N-ICE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Methamphetamine dependence 306846 0
Condition category
Condition code
Mental Health 305941 305941 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Take-home oral N-Acetyl-Cysteine, 2,400 mg per day, taken as 2 x 600 mg capsules morning and evening, for 12 weeks.
eCAP™ will be used as an objective measure of medication adherence. eCAP lids fitted to the medication bottle record the time of bottle opening, which will be downloaded at each interview using a CertiScan RFID desktop Reader or an NFC-enabled smart phone.
Intervention code [1] 300494 0
Treatment: Drugs
Comparator / control treatment
Placebo capsules containing microcrystalline cellulose, identical in appearance, taken in the same manner as the intervention medication,
Control group
Placebo

Outcomes
Primary outcome [1] 304982 0
Days of methamphetamine use in the past 4 weeks measured using the Timeline Followback (TLFB) aided by calendar diary updates at each weekly assessment
Timepoint [1] 304982 0
Baseline (week 0) and at weeks 4, 8, and 12 during the active trial medication phase. The primary analysis will include all time points in the active trial medication phase (i.e., weeks 4, 8 and 12).
Primary outcome [2] 304983 0
Percentage of methamphetamine positive saliva tests (=>25 ng/mL methamphetamine in saliva sample) taken during the active trial phase
Timepoint [2] 304983 0
Weekly, at weeks 1-12 during the active trial medication phase. All time-points will be included in the primary analysis.
Secondary outcome [1] 343799 0
Methamphetamine craving assessed as the total score on the Craving Experience Questionnaire (CEQ) for the past week
Timepoint [1] 343799 0
Weekly, at baseline (week 0) and at weeks 1-12 during the active trial medication phase
Secondary outcome [2] 343800 0
Severity of methamphetamine dependence, assessed as the total score on the Severity of Dependence Scale (SDS) for the past week
Timepoint [2] 343800 0
Weekly, at baseline (week 0) and at weeks 1-12 during the active trial medication phase
Secondary outcome [3] 343801 0
Methamphetamine withdrawal symptoms assessed as the total score on the Amphetamine Withdrawal Questionnaire (AWQ) for the past week
Timepoint [3] 343801 0
Weekly, at baseline (week 0) and at weeks 1-12 during the active trial medication phase
Secondary outcome [4] 343802 0
Symptoms of psychosis assessed as a score of 4 or greater on any of the Brief Psychiatric Rating Scale (BPRS) items of suspiciousness, unusual thought content or hallucinations for the past week
Timepoint [4] 343802 0
Weekly, at baseline (week 0) and at weeks 1-12 during the active trial medication phase
Secondary outcome [5] 343803 0
Hostility assessed as a score of 6-7 on the BPRS hostility item for the past week
Timepoint [5] 343803 0
Weekly, at baseline (week 0) and at weeks 1-12 during the active trial medication phase
Secondary outcome [6] 343804 0
Depression assessed as a score of 4+ on the BPRS depression item for the past week
Timepoint [6] 343804 0
Weekly, at baseline (week 0) and at weeks 1-12 during the active trial medication phase
Secondary outcome [7] 343805 0
Days using other drug classes (tobacco, alcohol, cannabis, cocaine, ecstasy, hallucinogens, inhalants, heroin), assessed using the Timeline Follow Back (TLBF) for the past 4 weeks, aided by calendar diary updates at each weekly assessment, and averaged across drug types.
Timepoint [7] 343805 0
Baseline (week 0) and at weeks 4, 8, and 12 during the active trial medication phase
Secondary outcome [8] 343881 0
Percentage of participants who report adverse events (AEs) and serious adverse events (SAEs)
Timepoint [8] 343881 0
Active trial medication phase from baseline to week 12
Secondary outcome [9] 348030 0
Suicidal ideation assessed as a score of 4+ on the BPRS suicidality item for the past week
Timepoint [9] 348030 0
Weekly, at baseline (week 0) and at weeks 1-12 during the active trial medication phase

Eligibility
Key inclusion criteria
• Aged between 18 and 60 years
• Dependent on methamphetamine (DSM-IV current diagnosis confirmed at baseline assessment using the Composite International Diagnostic Interview)
• Seeking to reduce methamphetamine use
• Willing to provide contact details for their general practitioner or other treating physician and their contact details for follow-up
• Able to provide informed consent and able to comply with both the requirements of the informed consent and the treatment protocol.
Minimum age
18 Years
Maximum age
60 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Currently enrolled in specialist treatment services for drug addiction (i.e., medically supervised detoxification, residential rehabilitation or drug counselling services, as defined in the Australian Minimum Dataset for Alcohol and Other Drug Treatment Services); this applies to the status of the participant at trial enrollment and does not preclude the participant from entering treatment or receiving usual care during the trial
• Currently enrolled in other pharmacotherapy for substance use disorders (including opioid substitution therapy, nicotine replacement therapy or other pharmacotherapy for nicotine or other stimulant dependence)
• In need of acute psychiatric care or an unstable psychiatric condition (e.g., suicidality or acute psychosis)
• In need of acute care for intoxication or in need of medically supervised detoxification
• A diagnosed primary psychotic disorder (schizophrenia, schizoaffective disorder, bipolar disorder)
• Currently taking medication or other preparations that contain NAC
• Contraindications for NAC:
- Previous hypersensitivity to NAC
- Pregnancy (confirmed at the baseline assessment) or lactation
- Unwillingness to use contraception to avoid pregnancy during the trial
- Currently taking medications thought to be hazardous if taken with NAC (e.g. carbamazepine, nitroglycerin)
- A known or suspected active systemic medical disorder including cancer, or medical condition, that may exacerbate the risk of adverse events from NAC (recent gastro-intestinal ulcers or renal stones, epilepsy or history of seizures, asthma or atopy)
- Recent surgery (within past 28 days).

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation will be based on a study ID allocated after the participant has been confirmed eligible following their baseline assessment and only after their first trial assessment (week 0) has been successfully scheduled. Trial medication will be dispensed and allocated sequentially according to the study ID contained in the randomisation schedule held by the trial site pharmacy. Packaging will be identical to conceal treatment allocation. All trial staff, the trial statistician and investigators will be blind to the condition. The analysis will be blind to condition. A statistical analysis plan will be finalized prior to unblinding.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation sequence is based on a 1:1 (treatment:placebo) permutated block randomisation, with variable block sizes, stratified by site (Melbourne, Geelong, Wollongong), gender (male vs. female) and main route of methamphetamine administration in the month prior to recruitment (injecting vs. not injecting) – factors known to affect methamphetamine treatment trial outcomes.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Sample size determination:

Our sample size (N = 180) is designed to detect a significant effect of trial medication on our primary endpoint of days of methamphetamine use. The expected effect size is based on data from the Methamphetamine Treatment Outcomes Study (MATES). Participants who did not receive treatment in this cohort showed a reduction in methamphetamine use from a mean±SD of 12.8±7.4 days/month at baseline to 6.0±6.7 days/month at 12 week follow-up. Our estimate of a minimal clinically meaningful reduction in use is based on outcomes for out-patient counselling derived from MATES: mean ±SD 11.2±8.8/month to 3.5±6.9/month at 12 weeks. To detect a between group difference of 6.0 vs. 3.5 days use, with 80% power and p < 0.025 (0.05/2 to accommodate two primary outcome measures), we need a sample of 72 per group at 12 weeks. Assuming an 80% follow-up rate at 12 weeks (based on our previous 81% follow-up in the MATES cohort) we need to recruit 90 participants per group (N = 180).

Analysis of primary endpoints:

The effect of NAC on the two primary methamphetamine use endpoints will be based on intention-to-treat (ITT) analyses.
- The effect of the trial medication on days of methamphetamine use (% of days used in the past 28 days) will be tested using a pre-test (Assessment 0) vs. post-test (3 repeats: Assessments 4, 8, and 12) by treatment condition (NAC vs. placebo) interaction.
- The effect of NAC on methamphetamine positive saliva will be tested using a main effect for treatment condition (NAC vs. placebo) on saliva test results (positive vs. negative) from Assessments 1-12 (12 repeats).
In both cases, effects will be tested with a mixed effect model with repeated measures (for each time-point of measurement). Heterogeneity of the treatment effect between sites will be tested for by seeing whether model fit is significantly improved (p < 0.05) by including a random intercept for site, and a random coefficient for the main effect by site, respectively. The most parsimonious model option will be adopted for the final analysis (this may include a random effects repeated measures regression model if no significant heterogeneity in the treatment effect is found between sites).

The main analysis will be based on imputed data. Missing data will be imputed using multiple imputation by chained equations. A secondary analysis will be done using unimputed data. Unobserved days (e.g., due to loss to follow-up, hospitalisation or incarceration during the follow-up period, or temporary discontinuation from the trial medication) will be censored from the analysis. Covariates to be included in the analysis, and procedures for adjustment, will be determined in the final Statistical Analysis Plan.

Analysis of secondary endpoints:

Analysis of secondary outcomes will be based on a modified ITT dataset. The modified ITT dataset will include participants who took at least one dose of trial medication (i.e. completed the baseline trial assessment (week 0) and received the trial medication) and who also have complete data on the relevant outcome for at least one follow-up assessment (i.e. weeks 1-12).
The analysis of secondary endpoints will use unimputed data. A sensitivity analysis will be conducted that uses imputed data. Missing data will be imputed using multiple imputation by chained equations.
The effect of NAC on each secondary outcome will be tested using a pre-test (baseline) vs. post-test (repeated measures for each weekly follow-up assessment) by treatment condition (NAC vs. placebo) interaction. Effects will be tested with a mixed effect model with repeated measures (for each time-point of measurement). Heterogeneity of the treatment effect will be tested for by seeing whether model fit is significantly improved (p < 0.05) by including a random intercept for site, and a random coefficient for the main effect by site, respectively. The most parsimonious model option will be adopted for the final analysis (this may include a random effects repeated measures regression model if no significant heterogeneity in the treatment effect between sites).

Safety analysis:

Data on adverse events (AEs) will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA). AEs will be counted once only for a given participant. The event counted will be the event with the highest severity (i.e., mild, moderate or severe). Safety analyses will report the number and percentage of participants reporting AEs and serious adverse events (SAEs) in each treatment condition, by System Organ Class (SOC); treatment conditions will be compared using a Pearson’s Chi-Square test. The safety analysis data set will include participants who took at least one dose of trial medication (i.e. completed their initial trial assessment and received the trial medication).

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
13/06/2018
Actual
9/07/2018
Date of last participant enrolment
Anticipated
29/11/2019
Actual
6/12/2019
Date of last data collection
Anticipated
30/04/2020
Actual
30/03/2020
Sample size
Target
180
Accrual to date
Final
153
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 10243 0
Wollongong Hospital - Wollongong
Recruitment hospital [2] 10244 0
Barwon Health - Geelong Hospital campus - Geelong
Recruitment hospital [3] 10245 0
Turning Point Drug and Alcohol Centre - Fitzroy
Recruitment postcode(s) [1] 21908 0
2500 - Wollongong
Recruitment postcode(s) [2] 21909 0
3220 - Geelong
Recruitment postcode(s) [3] 21910 0
3065 - Fitzroy

Funding & Sponsors
Funding source category [1] 298843 0
Government body
Name [1] 298843 0
National Health and Medical Research Council
Country [1] 298843 0
Australia
Primary sponsor type
University
Name
University of New South Wales
Address
University of New South Wales
Sydney 2052 NSW
Country
Australia
Secondary sponsor category [1] 298041 0
University
Name [1] 298041 0
Monash University
Address [1] 298041 0
Eastern Health Clinical School
Faculty of Medicine, Nursing and Health Sciences
Monash University
Level 2, 5 Arnold St
Box Hill VIC 3128
Australia
Country [1] 298041 0
Australia
Secondary sponsor category [2] 298052 0
University
Name [2] 298052 0
Burnet Institute
Address [2] 298052 0
85 Commercial Road, Melbourne
VIC, 3004, Australia
Country [2] 298052 0
Australia
Secondary sponsor category [3] 298053 0
University
Name [3] 298053 0
Deakin University
Address [3] 298053 0
221 Burwood Highway
Burwood VIC 3125
Australia
Country [3] 298053 0
Australia
Secondary sponsor category [4] 298054 0
University
Name [4] 298054 0
Wollongong University
Address [4] 298054 0
Northfields Ave
Wollongong NSW 2522
Australia
Country [4] 298054 0
Australia
Secondary sponsor category [5] 298055 0
University
Name [5] 298055 0
University of Newcaslte
Address [5] 298055 0
University Drive, Callaghan
NSW 2308, Australia
Country [5] 298055 0
Australia
Secondary sponsor category [6] 298056 0
University
Name [6] 298056 0
La Trobe University
Address [6] 298056 0
Cnr Plenty Rd & Kingsbury Dr,
Bundoora Victoria 3086
Australia
Country [6] 298056 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299786 0
Eastern Health
Ethics committee address [1] 299786 0
Office for Research and Ethics
Eastern Health
Box Hill Hospital
Level 2, 5 Arnold Street
Box Hill VIC 3128
Ethics committee country [1] 299786 0
Australia
Date submitted for ethics approval [1] 299786 0
16/11/2017
Approval date [1] 299786 0
19/04/2018
Ethics approval number [1] 299786 0
E21-2017 (Provisional approval granted on 21/11/2017)
Ethics committee name [2] 299797 0
University of Wollongong and the Illawarra Shoalhaven Local Health District (ISLHD) Human Research Ethics Committee
Ethics committee address [2] 299797 0
Research Services Office
Building 20, Level 1
University of Wollongong,
Northfields Ave
Wollongong NSW 2522
Ethics committee country [2] 299797 0
Australia
Date submitted for ethics approval [2] 299797 0
30/11/2017
Approval date [2] 299797 0
31/01/2018
Ethics approval number [2] 299797 0
2017/549
Ethics committee name [3] 299798 0
Research Ethics Governance and Integrity Unit, Barwon Health
Ethics committee address [3] 299798 0
PO Box 281, Geelong VIC 3220
Ethics committee country [3] 299798 0
Australia
Date submitted for ethics approval [3] 299798 0
13/12/2017
Approval date [3] 299798 0
20/04/2018
Ethics approval number [3] 299798 0
17/202 (conditional approval provided on 14/12/2017)
Ethics committee name [4] 299799 0
Monash University Human Research Ethics Committee
Ethics committee address [4] 299799 0
Monash University Human Research Ethics Committee
Monash University
Victoria 3800
Australia
Ethics committee country [4] 299799 0
Australia
Date submitted for ethics approval [4] 299799 0
16/03/2018
Approval date [4] 299799 0
19/04/2018
Ethics approval number [4] 299799 0
E21-2017
Ethics committee name [5] 299800 0
Curtin University Human Research Ethics Committee
Ethics committee address [5] 299800 0
Curtin University, Kent Street, Bentley, Perth, Western Australia 6102
Ethics committee country [5] 299800 0
Australia
Date submitted for ethics approval [5] 299800 0
16/03/2018
Approval date [5] 299800 0
03/05/2018
Ethics approval number [5] 299800 0
HRE2018-0205
Ethics committee name [6] 308200 0
University of New South Wales Human Research Ethics Committee
Ethics committee address [6] 308200 0
Sydney NSW 2052
Australia
Ethics committee country [6] 308200 0
Australia
Date submitted for ethics approval [6] 308200 0
05/09/2019
Approval date [6] 308200 0
12/09/2019
Ethics approval number [6] 308200 0
17/202 (Geelong site), E21-2017 (Melbourne site), 2017/549 (Wollongong site)

Summary
Brief summary
We will test the safety and efficacy of N-Acetyl-Cysteine (NAC) as a pharmacotherapy for methamphetamine dependence using a double-blind placebo-controlled randomised controlled trial (RCT). The trial will involve 180 participants receiving either 12 weeks of take-home oral NAC (2,400 mg daily) or equivalent placebo. There are three trial sites (Wollongong, Geelong and Melbourne). This is a Phase 2b trial that is powered to confirm whether NAC has a clinically relevant benefit on methamphetamine use and a range of related clinical outcomes.

Primary hypothesis: Daily oral NAC delivered as a take home medication will reduce methamphetamine use measured as (a) days of methamphetamine use, and (b) methamphetamine in weekly saliva tests, during 12 weeks of active treatment relative to placebo.

Secondary hypotheses: Daily oral NAC delivered as a take home medication will, relative to placebo:
- reduce the severity of methamphetamine dependence, craving for methamphetamine, methamphetamine withdrawal symptoms and psychiatric symptoms (affective symptoms, positive psychotic symptoms and hostility),
- have an acceptable adverse event profile, and
- not significantly increase the use of other substances (including alcohol, tobacco, cannabis, heroin and cocaine).
Trial website
www.nicetrial.info
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 81562 0
A/Prof Rebecca McKetin
Address 81562 0
National Drug and Alcohol Research Centre, University of New South Wales, Sydney 2052 NSW, Australia
Country 81562 0
Australia
Phone 81562 0
+61293850294
Fax 81562 0
+61 2 93850222
Email 81562 0
[email protected]
Contact person for public queries
Name 81563 0
Rebecca McKetin
Address 81563 0
National Drug and Alcohol Research Centre, University of New South Wales, Sydney 2052 NSW, Australia
Country 81563 0
Australia
Phone 81563 0
+61293850294
Fax 81563 0
+61 2 93850222
Email 81563 0
[email protected]
Contact person for scientific queries
Name 81564 0
Rebecca McKetin
Address 81564 0
National Drug and Alcohol Research Centre, University of New South Wales, Sydney 2052 NSW, Australia
Country 81564 0
Australia
Phone 81564 0
+61 2 93850294
Fax 81564 0
+61 2 93850222
Email 81564 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Confidentiality


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
4174Study protocolMcKetin, R., et al. (2019). "A study protocol for the N-ICE trial: A randomised double-blind placebo-controlled study of the safety and efficacy of N-acetyl-cysteine (NAC) as a pharmacotherapy for methamphetamine (“ice”) dependence." Trials 20(1): 325. https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-019-3450-0[email protected] 374626-(Uploaded-20-08-2019-10-21-33)-Study-related document.pdf
11201Statistical analysis planNot applicable   374626-(Uploaded-15-10-2020-12-16-35)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA study protocol for the N-ICE trial: A randomised double-blind placebo-controlled study of the safety and efficacy of N-acetyl-cysteine (NAC) as a pharmacotherapy for methamphetamine ("ice") dependence.2019https://dx.doi.org/10.1186/s13063-019-3450-0
Dimensions AIClinical and demographic characteristics of people who smoke versus inject crystalline methamphetamine in Australia: Findings from a pharmacotherapy trial2020https://doi.org/10.1111/dar.13183
EmbaseN-acetylcysteine (NAC) for methamphetamine dependence: A randomised controlled trial.2021https://dx.doi.org/10.1016/j.eclinm.2021.101005
N.B. These documents automatically identified may not have been verified by the study sponsor.