ANZCTR - Registration

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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 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]

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

Condition category

Condition code

Mental Health

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]

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]

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]

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]

Percentage of methamphetamine positive saliva tests (=>25 ng/mL methamphetamine in saliva sample) taken during the active trial phase

Timepoint [2]

Weekly, at weeks 1-12 during the active trial medication phase. All time-points will be included in the primary analysis.

Secondary outcome [1]

Methamphetamine craving assessed as the total score on the Craving Experience Questionnaire (CEQ) for the past week

Timepoint [1]

Weekly, at baseline (week 0) and at weeks 1-12 during the active trial medication phase

Secondary outcome [2]

Severity of methamphetamine dependence, assessed as the total score on the Severity of Dependence Scale (SDS) for the past week

Timepoint [2]

Weekly, at baseline (week 0) and at weeks 1-12 during the active trial medication phase

Secondary outcome [3]

Methamphetamine withdrawal symptoms assessed as the total score on the Amphetamine Withdrawal Questionnaire (AWQ) for the past week

Timepoint [3]

Weekly, at baseline (week 0) and at weeks 1-12 during the active trial medication phase

Secondary outcome [4]

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]

Weekly, at baseline (week 0) and at weeks 1-12 during the active trial medication phase

Secondary outcome [5]

Hostility assessed as a score of 6-7 on the BPRS hostility item for the past week

Timepoint [5]

Weekly, at baseline (week 0) and at weeks 1-12 during the active trial medication phase

Secondary outcome [6]

Depression assessed as a score of 4+ on the BPRS depression item for the past week

Timepoint [6]

Weekly, at baseline (week 0) and at weeks 1-12 during the active trial medication phase

Secondary outcome [7]

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]

Baseline (week 0) and at weeks 4, 8, and 12 during the active trial medication phase

Secondary outcome [8]

Percentage of participants who report adverse events (AEs) and serious adverse events (SAEs)

Timepoint [8]

Active trial medication phase from baseline to week 12

Secondary outcome [9]

Suicidal ideation assessed as a score of 4+ on the BPRS suicidality item for the past week

Timepoint [9]

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?

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]

Wollongong Hospital - Wollongong

Recruitment hospital [2]

Barwon Health - Geelong Hospital campus - Geelong

Recruitment hospital [3]

Turning Point Drug and Alcohol Centre - Fitzroy

Recruitment postcode(s) [1]

2500 - Wollongong

Recruitment postcode(s) [2]

3220 - Geelong

Recruitment postcode(s) [3]

3065 - Fitzroy

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

National Health and Medical Research Council

Address [1]

GPO Box 1421
Canberra ACT 2601

Country [1]

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]

University

Name [1]

Monash University

Address [1]

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]

Australia

Secondary sponsor category [2]

University

Name [2]

Burnet Institute

Address [2]

85 Commercial Road, Melbourne
VIC, 3004, Australia

Country [2]

Australia

Secondary sponsor category [3]

University

Name [3]

Deakin University

Address [3]

221 Burwood Highway
Burwood VIC 3125
Australia

Country [3]

Australia

Secondary sponsor category [4]

University

Name [4]

Wollongong University

Address [4]

Northfields Ave
Wollongong NSW 2522
Australia

Country [4]

Australia

Secondary sponsor category [5]

University

Name [5]

University of Newcaslte

Address [5]

University Drive, Callaghan
NSW 2308, Australia

Country [5]

Australia

Secondary sponsor category [6]

University

Name [6]

La Trobe University

Address [6]

Cnr Plenty Rd & Kingsbury Dr,
Bundoora Victoria 3086
Australia

Country [6]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Eastern Health

Ethics committee address [1]

Office for Research and Ethics
Eastern Health 
Box Hill Hospital
Level 2, 5 Arnold Street
Box Hill VIC 3128

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

16/11/2017

Approval date [1]

19/04/2018

Ethics approval number [1]

E21-2017 (Provisional approval granted on 21/11/2017)

Ethics committee name [2]

University of Wollongong and the Illawarra Shoalhaven Local Health District (ISLHD) Human Research Ethics Committee

Ethics committee address [2]

Research Services Office
Building 20, Level 1
University of Wollongong,
Northfields Ave
Wollongong NSW 2522

Ethics committee country [2]

Australia

Date submitted for ethics approval [2]

30/11/2017

Approval date [2]

31/01/2018

Ethics approval number [2]

2017/549

Ethics committee name [3]

Research Ethics Governance and Integrity Unit, Barwon Health

Ethics committee address [3]

PO Box 281, Geelong VIC 3220

Ethics committee country [3]

Australia

Date submitted for ethics approval [3]

13/12/2017

Approval date [3]

20/04/2018

Ethics approval number [3]

17/202 (conditional approval provided on 14/12/2017)

Ethics committee name [4]

Monash University Human Research Ethics Committee

Ethics committee address [4]

Monash University Human Research Ethics Committee
Monash University
Victoria 3800
Australia

Ethics committee country [4]

Australia

Date submitted for ethics approval [4]

16/03/2018

Approval date [4]

19/04/2018

Ethics approval number [4]

E21-2017

Ethics committee name [5]

Curtin University Human Research Ethics Committee

Ethics committee address [5]

Curtin University, Kent Street, Bentley, Perth, Western Australia 6102

Ethics committee country [5]

Australia

Date submitted for ethics approval [5]

16/03/2018

Approval date [5]

03/05/2018

Ethics approval number [5]

HRE2018-0205

Ethics committee name [6]

University of New South Wales Human Research Ethics Committee

Ethics committee address [6]

Sydney NSW 2052
Australia

Ethics committee country [6]

Australia

Date submitted for ethics approval [6]

05/09/2019

Approval date [6]

12/09/2019

Ethics approval number [6]

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

A/Prof Rebecca McKetin

Address

National Drug and Alcohol Research Centre, University of New South Wales, Sydney 2052 NSW, Australia

Country

Australia

Phone

+61293850294

Fax

+61 2 93850222

[email protected]

Contact person for public queries

Name

Rebecca McKetin

Address

National Drug and Alcohol Research Centre, University of New South Wales, Sydney 2052 NSW, Australia

Country

Australia

Phone

+61293850294

Fax

+61 2 93850222

[email protected]

Contact person for scientific queries

Name

Rebecca McKetin

Address

National Drug and Alcohol Research Centre, University of New South Wales, Sydney 2052 NSW, Australia

Country

Australia

Phone

+61 2 93850294

Fax

+61 2 93850222

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

Confidentiality

What supporting documents are/will be available?

Doc. No.	Type	Citation	Link	Email	Other Details	Attachment
4174	Study protocol	McKetin, 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
11201	Statistical analysis plan	Not applicable				374626-(Uploaded-15-10-2020-12-16-35)-Study-related document.pdf

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	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.	2019	https://dx.doi.org/10.1186/s13063-019-3450-0
Dimensions AI	Clinical and demographic characteristics of people who smoke versus inject crystalline methamphetamine in Australia: Findings from a pharmacotherapy trial	2020	https://doi.org/10.1111/dar.13183
Embase	N-acetylcysteine (NAC) for methamphetamine dependence: A randomised controlled trial.	2021	https://dx.doi.org/10.1016/j.eclinm.2021.101005

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically