Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000762752
Ethics application status
Approved
Date submitted
2/08/2021
Date registered
27/05/2022
Date last updated
2/03/2023
Date data sharing statement initially provided
27/05/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
Theta burst Transcranial Magnetic Stimulation for Methamphetamine use disorder (TARTAN)
Scientific title
Theta burst Transcranial Magnetic Stimulation (TMS) for Methamphetamine use disorder– A feasibility study to inform a multi-site Randomised Control Trial
Secondary ID [1] 304926 0
None
Universal Trial Number (UTN)
Trial acronym
TARTAN
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Amphetamine use disorder 323073 0
Condition category
Condition code
Mental Health 320652 320652 0 0
Addiction

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Stimulation Localisation: Scalp locations at which the TMS coil will be placed will be determined using standard EEG 10-20 system landmarks.

These two locations are:
Intermittent TBS (iTBS) to the left Dorso Lateral Pre Frontal Cortex (DLPFC): Treatment will be localised at the F3 EEG site which corresponds to left DLPFC.
Continuous TBS (cTBS) to the left Orbito Frontal Cortex (OFC): Treatment will be localised at the FP1 EEG site which corresponds to the left OFC.

Provision of intervention
TBS will be administered with a TGA registered TMS device (Neuro-MSD and Angulated Fig8 Coil). Prior to the commencement of TBS treatment, single pulse TMS will be used to measure the resting motor thresholds (RMT) for the abductor pollicis brevis (APB) in all subjects using standard published methods. The RMT is used to determine the intensity of the TBS treatment for each individual participant

Stimulation Parameters: TBS intervention
Protocol A. First. iTBS will be delivered at the Left DLPFC(F3) as 3-pulse 50-Hz bursts applied at 5 Hz (i.e. 50 Hz burst of 3 pulses delivered every 200ms) with a 2-second train of TBS repeated every 10 seconds (i.e. 2 seconds of TBS followed by an 8 second rest). Total number of pulses is 600. Each TBS treatment session will take approximately 3 minutes. During the initial treatment sessions, the amplifier output will be escalated (over 30 sec) from 70% to 110% RMT to enhance tolerability. For clients who experience discomfort and are not able to comfortably tolerate increases in intensity, the level will be maintained at the maximally tolerable level. Participants will be withdrawn if they are unable to tolerate treatment at a minimum 70% of the RMT at the end of the 3rd day of treatment.
Protocol B. Second: Following this, cTBS will be delivered at the left OFC: A single train of cTBS will be applied over the left frontal pole (Fp1) (3 pulse 50 Hz bursts applied at 5Hz, 15 pulses/sec, 600 pulses/train; 100% RMT. During the cTBS procedure the amplifier output will be escalated during the first train (over 30 sec) from 70% to 100% RMT to enhance tolerability. For clients who experience discomfort and are not able to comfortably tolerate this intensity, the level will progressively be decreased until a comfortable intensity is reached. Participants will be withdrawn if they are unable to tolerate treatment at 70% of the RMT at the end of the 3rd day of treatment.

Then there is a 10 minute interval and Protocol A and B are repeated.
Then protocol A and protocol B will be repeated for another two cycles in a treatment day with 10 minute intervals after protocol B (that is three cycles of Protocol A and B in a treatment day) if tolerated.

TBS will be provided on three days of each week for a total of four weeks for each participant (that is a total of 12 sessions of TMS over four weeks).

Medical specialists (Addiction Psychiatrists and Addiction Medicine Specialists) will screen patients and establish treatment parameters for each patient and do the first treatment. Clinical research officers under the supervision of medical specialists will deliver subsequent interventions. All will have a certificate of accreditation by Neurocare for delivery of TMS (course: rTMS for Depression, OCD & New Developments).

Location of the intervention: Clinical Research rooms, Level 3, Newcastle Community Health Centre, 670 Hunter Street, Newcastle, NSW 2300.

Counselling: All participants will be offered standard care for MA use disorders, involving psychosocial counselling (of approximately 50 minutes) for the duration of the study and referral to appropriate services post study as clinically indicated. Importantly, study related counselling sessions will provide support to participants through psychoeducation into the neurocircuitry of MA use disorder, relapse prevention for MA dependence and TMS treatment adherence. Counselling sessions will be offered face to face or by telehealth or telephone as requested. Clients will be offered one counselling session per week during the 4 weeks of treatment. Counselling will be performed by a trained HNELHD Drug and Alcohol Clinical Services counsellor independent of the study. Counselling will be standardised using an established protocol for Cognitive Behavioural Therapy for MA use disorder, and one counsellor independent of the TMS research team will deliver the sessions as per the standardised counselling protocol.

Data. Every client will have an individual case record where adherence to each of the 12 TMS sessions is recorded (including partial treatment or missed sessions recorded), and adherence to the four counselling sessions will be recorded.
Intervention code [1] 321323 0
Treatment: Devices
Comparator / control treatment
Sham (non-functional contSham intervention
For this study, we will utilise the integrated Sham stimulation system in the Neuro-MS.NET software which allows sham stimulation to be delivered by electrodes that create a proportional sensory stimulation to the real TMS intervention. The electrodes will be placed on the exact same location for both the groups near the coil.. The TMS coil will only deliver stimulation in the active arm. Control arm (Sham) blinding is achieved by the synchronous sound masking performed created using a speaker located near the discharging coil. The synchronous electrical stimulation is given through electrodes fixed on the head along the front edge of the coil to mimic the sensation. The electrical stimulation amplitude for TMS-naïve subjects was from 2 to 5 mA, providing superficial sensations but not CNS stimulation. This software has been validated by Neurosoft as providing effective blinding for TMS-naïve subjects, and to a lesser extent, TMS experience participants. For this study, we will exclude participants who have experience using TMS.
Control group
Placebo

Outcomes
Primary outcome [1] 328468 0
Assess the feasibility of using TMS for the treatment of moderate- severe MA use disorder> This will be done by documentation of the following:
• Proportion of potential participants (of total referrals to the study) that fit the study inclusion criteria
• Proportion of eligible participants willing to be randomised
• Proportion of consenting participants that complete all baseline assessments within assessment period
• Proportion of consenting participants that commence allocated intervention
• Proportion of consenting participants that complete TMS and follow-up assessment at week 4.

Data is collected at the time of screening and treatment via the use of electronic data capture in the form of REDCap (Research Electronic Data Capture). The REDCap database is located on a standalone database server hosted by Hunter New England Local Health District (HNELHD). The database server resides behind the HNELHD internal firewall and access to the server is controlled via firewall rules. All data collected via REDCap is backed up daily, both on the local server and by the HNELHD backup system. All connections to the system, both external and internal, will occur over encrypted channels.
Access to study records within the study database has been limited by using Data Access Groups (DAGS). Only users within a given DAGs can access records created by users within that group. Access to components of study records is role-based and can only be granted by the Project Manager of the study.
All data entered into REDCap for the purpose of data analyses will be de-identified and traceable to supporting identifiable source documentation such as hospital/medical records (including electronic health records), laboratory results, data recorded in automated instruments and pharmacy records, etc. All source documentation will be held confidentially in line with current legislation governing health information and will not be made publicly available. All study documentation (electronic and paper copies) will be archived securely at the end of the study for 15 years and then destroyed by secure destruction. The TMS device will also capture treatment parameters (intensity, duration, protocol) for each treatment session for each participant. This data will be exported at the end of the study..
Timepoint [1] 328468 0
At the final assessment after the fouth week of treatment (end of fourth week) from the first treatment session.
Primary outcome [2] 328469 0
Assess the safety of TMS for the treatment of moderate- severe MA use disorder.

Adverse events monitoring log will be used to capture all adverse events. Any spontaneously reported adverse events will be recorded after the subject signs the informed consent form. In addition Adverse Events will be elicited using non-leading questions.
Timepoint [2] 328469 0
Spontaneously reported adverse events will be recorded after the subject signs the informed consent form.
In addition Adverse Events will be elicited using non-leading questions at the time points identified (at each TMS session during the 4 weeks of treatment). The last will be at the end of the four weeks of treatment (day 28 from the first treatment session).
Secondary outcome [1] 399106 0
To examine treatment adherence of participants for use of TMS for MA use disorder.

Data is collected at the time of screening and treatment via the use of electronic data capture in the form of REDCap (Research Electronic Data Capture). All data entered into REDCap for the purpose of data analyses will be de-identified and traceable to supporting identifiable source documentation such as hospital/medical records (including electronic health records), laboratory results, data recorded in automated instruments and pharmacy records, etc. All source documentation will be held confidentially in line with current legislation governing health information and will not be made publicly available. All study documentation (electronic and paper copies) will be archived securely at the end of the study for 15 years and then destroyed by secure destruction. The TMS device will also capture treatment parameters (intensity, duration, protocol) for each treatment session for each participant. This data will be exported at the end of the study..
Timepoint [1] 399106 0
• Proportion of consenting participants that complete three, six, nine and 12 TMS treatment sessions within one, two, three and four weeks respectively from the first session of TMS.
Secondary outcome [2] 399107 0
Assess changes in MA use (instrument: self-reported use via timeline follow back at weeks one, two, three and four, and Urine Drug Screen at baseline, week 3 and end of treatment, from the first session of TMS).
Timepoint [2] 399107 0
at baseline, week 3 and end of treatment, from the first session of TMS.
Secondary outcome [3] 399108 0
To assess patient experiences with use of TMS for MA use disorder.:

Instrument: A short structured survey will be conducted at the end of treatment to assess treatment acceptability. Survey questions have been developed by study investigators and based on the seven domains recommended by the Theoretical Framework of Acceptability (Sekhon et al., 2017). Two open-ended options are included forcomprehensive responsesand clarification purposes.
Timepoint [3] 399108 0
After the last session of TMS (that is end of fourth week from the first TMS session).
Secondary outcome [4] 399109 0
Outcome: To examine differences in brain neurocircuitry and processes (using functional MRI) involved in drug cue elicited cravings in people with moderate to severe MA use disorder.
Timepoint [4] 399109 0
At baseline prior to the first TMS session and after the last TMS session at the end of the fourth week of treatment (from the first TMS session).
Secondary outcome [5] 404604 0
To examine treatment adherence rates of participants for councelling for MA use disorder..
Data is collected at the time of screening and treatment via the use of electronic data capture in the form of REDCap (Research Electronic Data Capture). All data entered into REDCap for the purpose of data analyses will be de-identified and traceable to supporting identifiable source documentation such as hospital/medical records (including electronic health records), laboratory results, data recorded in automated instruments and pharmacy records, etc. All source documentation will be held confidentially in line with current legislation governing health information and will not be made publicly available. All study documentation (electronic and paper copies) will be archived securely at the end of the study for 15 years and then destroyed by secure destruction.
Timepoint [5] 404604 0
Proportion of consenting participants that complete up to four counselling sessions by end of week 4 (from the first TMS treatment session)..
Secondary outcome [6] 404605 0
To assess the impact of TMS on cravings in patients with MA use disorder..

Assess cue-induced craving measured following exposure to a cue reactivity paradigm (presentation of a series of MA-related and neutral visual stimuli) with self-report craving assessed pre and post paradigm using visual analogue scale (VAS).
Timepoint [6] 404605 0
At baseline and end of treatment at four weeks (from the first TMS session).
Secondary outcome [7] 404606 0
To assess the impact of TMS on cognition (response inhibition) in patients with MA use disorder.

Instruments: Go/NoGo task
Timepoint [7] 404606 0
At baseline and end of treatment at four weeks (from the first TMS session).

Eligibility
Key inclusion criteria
• Aged 18-65 years
• Meets DSM 5 criteria for moderate to severe MA use disorder
• Current MA past month use
• Able to give written informed consent
• Be willing and able to comply with the requirements of the study
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Other psychoactive substance use requiring withdrawal management pharmacotherapy in the 28 days preceding eligibility screening (e.g. alcohol withdrawal requiring diazepam)
• Current pharmacotherapy for amphetamine use disorder (e.g. dexamphetamine) in the 28 days preceding eligibility screening.
• Current diagnosis of bipolar disorder, schizoaffective disorder, schizophrenia, that is deemed by research team psychiatrists not to have been drug-induced. Psychotic disorder not associated with drug use per DSM 5 criteria. Psychosis not otherwise specified (NOS), in remission, or drug-induced psychotic episodes are not exclusion criteria since these may be related to methamphetamine misuse.
• Severe uncontrolled medical condition, diagnosis of neurological disorder or neurocognitive disorder. Prior neurosurgical procedure.
• Contraindications to TMS (e.g. patients with epilepsy or seizure disorder, patients with implanted ferromagnetic equipment in their face or skull near the stimulation target, Cochlear implants, metal implant or electronic devices in the head, brain aneurysm clips/coils, VNS, pacemakers, deep brain stimulation, VP shunts, brain or neck stents, epilepsy, medical pump, hearing disorder, recent head injury).
• Current or planned pregnancy
• History of ECT treatment within the past three months.
• History of any previous TMS treatment.

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)
No
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation)
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
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
As a feasibility study data will be summarised by descriptive statistics for all outcome measures. Frequency counts and proportions will be used for categorical variables, and mean, range, interquartile range and 95 % confidence interval of mean for continuous variables reported.
Outcomes will be summarised across the intervention and control arms of this study. The feasibility of completing the study protocol and measures will be assessed. A sample size of 30 participants is sufficient to allow a reasonable estimate of feasibility and proportion completion of study protocol and measures.

For the purpose of informing a future multisite RCT, the effect of BS on all continuous outcomes (cue-induced craving, days of MA use, scores on cognitive tests, patient satisfaction, and staff perception) will be estimated by comparing mean change in the outcome in question in the sham group to mean change in the TBS group. For each outcome change scores will be calculated at 4 weeks. Change scores will be calculated by subtracting each participant’s score at 4 weeks from their score at baseline. Welch’s two sample t-test will be used to test these group differences. Differences in rates of dropout from treatment will be estimated using Cox’s proportional hazards regression and Kaplan Meier plots. Group differences in odds of experiencing any of the binary events (e.g. completing all follow-up assessments, commencing allocated intervention) will be estimated via binomial regression.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
30/05/2022
Actual
23/05/2022
Date of last participant enrolment
Anticipated
30/04/2023
Actual
Date of last data collection
Anticipated
31/05/2023
Actual
Sample size
Target
30
Accrual to date
1
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 20124 0
Drug and Alcohol Clinical Services, Hunter New England Local Health District - Newcastle
Recruitment postcode(s) [1] 34835 0
2300 - Newcastle

Funding & Sponsors
Funding source category [1] 309306 0
Other Collaborative groups
Name [1] 309306 0
National Centre for Clinical Research on Emerging Drugs (NCCRED) and Commonwealth of Australia
Country [1] 309306 0
Australia
Funding source category [2] 309307 0
University
Name [2] 309307 0
Centre for Brain & Mental Health Research (CBMHR)
Country [2] 309307 0
Australia
Primary sponsor type
Government body
Name
Hunter New England Local Health District Drug and Alcohol Clinical Services
Address
Level 3, 670 Hunter Street, Newcastle, NSW 2300
Country
Australia
Secondary sponsor category [1] 310280 0
None
Name [1] 310280 0
Address [1] 310280 0
Country [1] 310280 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309136 0
Hunter New England Human Research Ethics Committee
Ethics committee address [1] 309136 0
Ethics committee country [1] 309136 0
Australia
Date submitted for ethics approval [1] 309136 0
02/08/2021
Approval date [1] 309136 0
19/10/2021
Ethics approval number [1] 309136 0
2021/ETH11047

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

Contacts
Principal investigator
Name 113110 0
Dr Buddhima Lokuge
Address 113110 0
Hunter New England Drug and Alcohol Clinical Services, Level 3, 670 Hunter Street, Newcastle, NSW 2300
Country 113110 0
Australia
Phone 113110 0
+61240164781
Fax 113110 0
+61240164661
Email 113110 0
Buddhima.Lokuge@health.nsw.gov.au
Contact person for public queries
Name 113111 0
Melinda Jackson
Address 113111 0
Hunter New England Drug and Alcohol Clinical Services, Level 3, 670 Hunter Street, Newcastle, NSW 2300
Country 113111 0
Australia
Phone 113111 0
+61240164675
Fax 113111 0
+61240164661
Email 113111 0
mel.jackson@health.nsw.gov.au
Contact person for scientific queries
Name 113112 0
Buddhima Lokuge and Tarun Yadav
Address 113112 0
Hunter New England Drug and Alcohol Clinical Services, Level 3, 670 Hunter Street, Newcastle, NSW 2300
Country 113112 0
Australia
Phone 113112 0
+61240164781
Fax 113112 0
+61240164661
Email 113112 0
Buddhima.Lokuge@health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Consent not obtained for this use


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.