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Trial registered on ANZCTR


Registration number
ACTRN12622000235707
Ethics application status
Approved
Date submitted
29/01/2022
Date registered
9/02/2022
Date last updated
28/01/2024
Date data sharing statement initially provided
9/02/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
The Tina Trial: A trial of mirtazapine for methamphetamine dependence
Scientific title
The Tina Trial: A phase 3 randomised placebo-controlled trial of mirtazapine as a pharmacotherapy for methamphetamine (“ice”) dependence
Secondary ID [1] 305964 0
Nil Known
Universal Trial Number (UTN)
U1111-1271-8220
Trial acronym
Tina
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Methamphetamine dependence 324564 0
Condition category
Condition code
Mental Health 322031 322031 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Oral mirtazapine tablets (30 mg) once per day for 12 weeks. Adherence will be monitored using MEMS® SmartCaps.
Excipients consisting of:
- Microcrystalline cellulose
- Lactose monohydrate
- Croscarmellose sodium
- Magnesium stearate
- Hypromellose
- Hyprolose
- Macrogol 8000
- Titanium dioxide
- Iron oxide colouring
Intervention code [1] 322356 0
Treatment: Drugs
Comparator / control treatment
Matched placebo tablet consisting of the following excipients:
• Microcrystalline Cellulose
• Colloidal silicon dioxide
• Sodium starch glycolate
• Sodium stearyl fumarate
• Opadry coating solution
Control group
Placebo

Outcomes
Primary outcome [1] 329787 0
Change in self-reported days of methamphetamine use in the past 28 days from baseline to week 12, assessed using the Timeline Followback (TLFB).
Timepoint [1] 329787 0
Baseline, week 4, week 8, week 12 (primary timepoint) and week 20 after intervention commencement.
Secondary outcome [1] 403760 0
Methamphetamine negative oral fluid samples (< 25 ng/mL methamphetamine)
Timepoint [1] 403760 0
Week 4, week 8, and week 12 after intervention commencement.
Secondary outcome [2] 403761 0
Depression: total score on the Patient Health Questionnaire-9 (PHQ-9).
Timepoint [2] 403761 0
Baseline, week 4, week 8, week 12 and week 20 after intervention commencement.
Secondary outcome [3] 403762 0
Sleep Quality: Total score on the Athens Insomnia Scale (AIS)
Timepoint [3] 403762 0
Baseline, week 4, week 8, week 12 after intervention commencement.
Secondary outcome [4] 403763 0
HIV risk behaviour: Total score on a modified version of the HIV Risk Behaviour Scale from the Opiate Treatment Index
Timepoint [4] 403763 0
Baseline, week 4, week 8, week 12 after intervention commencement.
Secondary outcome [5] 405377 0
Quality of life: Utility score on the EuroQol-5D-5L (EQ-5D)
Timepoint [5] 405377 0
Baseline and weeks 4, 8 and 12 after intervention commencement.

Eligibility
Key inclusion criteria
• Aged between 18 and 65 years
• Moderate to severe methamphetamine use disorder in the past year (DSM-5 past year
diagnosis confirmed at Eligibility. Assessment using the Composite International
Diagnostic Interview)
• Current methamphetamine use (defined as using at least twice weekly in past 4 weeks
based on the participant’s self-reported use, and a positive drug screening test for
methamphetamine)
• Willing to use effective contraception (for women only)
• Willing to provide contact details for their treating physician
• Willing to provide 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
Answer to query:
The change in diagnostic criteria was made prior to any recruitment commencing. The change was made on protocol Version 5, dated 06/09/2022.
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• In need of acute care (e.g., suicidality or acute psychosis, unstable psychiatric
condition; medical detoxification)
• Pregnant or lactating
• Incarceration or current inpatient treatment (including residential rehabilitation,
inpatient detoxification); this applies to the status of the participant at trial enrolment
and does not preclude the participant from entering treatment or receiving usual care
during the trial
• Contraindications for mirtazapine, including:
o Known hypersensitivity to mirtazapine
o Use of antidepressant medication (including monoamine oxidase inhibitors, St.
John’s Wort, or SSRIs) other serotonergic drugs.
• High risk of adverse reactions to mirtazapine including suicide, overdose, sudden
cardiac death, risk of agranulocytosis, or accidents and injuries from motor impairment
• Past year suicide attempt
• Unable or unwilling to avoid pregnancy during the trial
• Participation in another clinical trial

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 to each participant after they have been confirmed eligible. Trial medication will be dispensed and allocated according to the study ID contained in the randomisation schedule, which will be generated by an independent statistician and 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. A statistical analysis plan will be finalized prior to unblinding. The analysis of will be blind to condition.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomly assigned to receive either the placebo or mirtazapine based on a computer generated randomisation sequence. The randomisation sequence is based on a 1::1 (treatment:placebo) permutated block randomisation, with variable block sizes, stratified by site site (Geelong, Wollongong, Perth, Brisbane, other), gender (male vs. female) and depression (PHQ-9 score < 10 vs. 10 or greater)..
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 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample size determination:

Our sample size (N = 340; 170 per group) will enable us to detect a minimum rate ratio of 0.75 on our primary outcome (equivalent to a reduction from 25 days methamphetamine use in the past month to 20 days use) with 90% power (two-tailed test, p = 0.05). This sample size calculation is based on the effect size found in the most recent trial of mirtazapine for methamphetamine dependence (Coffin et al.) and allows for up to 25% attrition.

Analysis of primary and secondary efficacy endpoints:

A Statistical Analysis Plan will be written prior to unblinding of the data which will confirm the final analysis strategy.
The main analysis of both the primary and secondary endpoints will be based on unimputed data. Sensitivity analyses will use multiple imputations using chained equations to impute missing data. All tests will be two-sided with p < 0.05.

Primary endpoint:

The analyses of the primary endpoint will be based on participants who took at least one dose of study medication. The primary timepoint being week 12. The main effect of medication on methamphetamine use days will be tested using a mixed model with a group (placebo vs. mirtazapine) by time (baseline, week 4, week 8, week 12) interaction effect, with time entered as a factor variable, producing individual effect estimates for each time point and making no assumptions about linear changes over time.

Secondary endpoints:

The analyses of the secondary endpoints will be based on participants who took at least one dose of the study medication and who were not lost to follow-up (i.e., had at least one follow-up data point).
The analyses methamphetamine negative oral fluid samples (no [0], yes [1]) will be tested using a mixed model with a group contrast (placebo vs. mirtazapine) across all follow-up time points (weeks 4, 8 and 12) to obtain an average treatment effect. The outcome will be repeated measures of whether the participants had a negative oral fluid sample (no[0], yes[1]) at each timepoint.
The effect of mirtazapine on other secondary endpoints (depression, sleep, quality of life and HIV risk) will be tested with a mixed model using a group (placebo vs. mirtazapine) by time (baseline vs. follow-up [weeks 4, 8 and 12]) with time entered as a factor variable, producing individual effect estimates for each time point and making no assumptions about linear changes over time. The primary timepoint for these endpoints will be week 12.

Safety analysis:

Safety analyses will report the number and percentage of participants reporting adverse events (AEs) and serious adverse events (SAEs) in each treatment group, by System Organ Class (SOC). Treatment conditions will be compared using a Pearson’s Chi-Square test.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
19/09/2022
Actual
16/11/2022
Date of last participant enrolment
Anticipated
30/11/2024
Actual
Date of last data collection
Anticipated
30/05/2025
Actual
Sample size
Target
340
Accrual to date
148
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA,VIC
Recruitment hospital [1] 21573 0
Biala City Community Health Centre - Brisbane
Recruitment hospital [2] 21574 0
Next Step Community Alcohol and Drug Service East Perth - East Perth
Recruitment hospital [3] 21575 0
Illawarra Drug and Alcohol Service - Wollongong
Recruitment hospital [4] 21576 0
Drug and Alcohol Services- Barwon Health - Geelong
Recruitment postcode(s) [1] 36493 0
4000 - Brisbane
Recruitment postcode(s) [2] 36494 0
6004 - East Perth
Recruitment postcode(s) [3] 36495 0
2500 - Wollongong
Recruitment postcode(s) [4] 36496 0
3220 - Geelong

Funding & Sponsors
Funding source category [1] 310306 0
Government body
Name [1] 310306 0
The National Health and Medical Research Council (Medical Research Future Fund)
Country [1] 310306 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] 311424 0
University
Name [1] 311424 0
Wollongong University
Address [1] 311424 0
Northfields Ave
Wollongong NSW 2522
Country [1] 311424 0
Australia
Secondary sponsor category [2] 311425 0
University
Name [2] 311425 0
The University of Sydney
Address [2] 311425 0
City Road, Camperdown/Darlington NSW 2006.
Country [2] 311425 0
Australia
Secondary sponsor category [3] 311426 0
University
Name [3] 311426 0
Deakin University
Address [3] 311426 0
221 Burwood Highway
Burwood VIC 3125
Country [3] 311426 0
Australia
Secondary sponsor category [4] 311427 0
University
Name [4] 311427 0
Monash University
Address [4] 311427 0
Monash University
Clayton
Victoria 3800
Country [4] 311427 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309968 0
University of Wollongong and the Illawarra Shoalhaven Local Health District (ISLHD) Human Research Ethics Committee
Ethics committee address [1] 309968 0
Ethics committee country [1] 309968 0
Australia
Date submitted for ethics approval [1] 309968 0
13/01/2022
Approval date [1] 309968 0
06/05/2022
Ethics approval number [1] 309968 0
2021/ETH12037
Ethics committee name [2] 309969 0
North Metropolitan Health Service Mental Health Research Ethics and Governance Office (NMHSMH REGO)
Ethics committee address [2] 309969 0
Ethics committee country [2] 309969 0
Australia
Date submitted for ethics approval [2] 309969 0
16/03/2022
Approval date [2] 309969 0
02/06/2022
Ethics approval number [2] 309969 0
RGS0000005312
Ethics committee name [3] 310203 0
Royal Brisbane and Women’s Hospital Human Research Ethics Committee, Metro North Health
Ethics committee address [3] 310203 0
Ethics committee country [3] 310203 0
Australia
Date submitted for ethics approval [3] 310203 0
16/03/2022
Approval date [3] 310203 0
Ethics approval number [3] 310203 0
Ethics committee name [4] 310204 0
Research Ethics Governance and Integrity Unit, Barwon Health
Ethics committee address [4] 310204 0
Ethics committee country [4] 310204 0
Australia
Date submitted for ethics approval [4] 310204 0
16/03/2022
Approval date [4] 310204 0
Ethics approval number [4] 310204 0
Ethics committee name [5] 310216 0
University of New South Wales Research Ethics Committee A
Ethics committee address [5] 310216 0
Ethics committee country [5] 310216 0
Australia
Date submitted for ethics approval [5] 310216 0
16/03/2022
Approval date [5] 310216 0
Ethics approval number [5] 310216 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 116022 0
A/Prof Rebecca McKetin
Address 116022 0
National Drug and Alcohol Research Centre, University of New South Wales, Sydney 2052 NSW
Country 116022 0
Australia
Phone 116022 0
+61 293850294
Fax 116022 0
+61 2 93850222
Email 116022 0
[email protected]
Contact person for public queries
Name 116023 0
Rebecca McKetin
Address 116023 0
National Drug and Alcohol Research Centre, University of New South Wales, Sydney 2052 NSW
Country 116023 0
Australia
Phone 116023 0
+61 293850294
Fax 116023 0
+61 2 93850222
Email 116023 0
[email protected]
Contact person for scientific queries
Name 116024 0
Rebecca McKetin
Address 116024 0
National Drug and Alcohol Research Centre, University of New South Wales, Sydney 2052 NSW
Country 116024 0
Australia
Phone 116024 0
+61 293850294
Fax 116024 0
+61 2 93850222
Email 116024 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified data, study protocol and data dictionary.
When will data be available (start and end dates)?
From 12 months after the end date of the study on request and approval of the Sponsor. No anticipated end-date for data access.
Available to whom?
All study investigators will be provided with access to de-identified study data after unblinding of the data. De-identified data may be provided by study investigators to third parties for the purposes of research, provided that this is in accordance with ethics approvals.
Available for what types of analyses?
Research analyses
How or where can data be obtained?
By application to the Sponsor. (Please contact the Sponsor's Delegate Rebecca McKetin [email protected] for details.)


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.