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Trial registered on ANZCTR


Registration number
ACTRN12621000342819
Ethics application status
Approved
Date submitted
11/01/2021
Date registered
25/03/2021
Date last updated
25/03/2021
Date data sharing statement initially provided
25/03/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Transcranial Magnetic Stimulation and Oral Ketamine Combination Treatment for
Post-Traumatic Stress Disorder (TMS-OK PTSD)
Scientific title
The Effect of Transcranial Magnetic Stimulation and Oral Ketamine Combination Treatment on severity of symptoms in Post-Traumatic Stress Disorder (TMS-OK PTSD)
Secondary ID [1] 301798 0
None
Universal Trial Number (UTN)
Trial acronym
TMS-OK PTSD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post-traumatic stress disorder 318274 0
Condition category
Condition code
Mental Health 316290 316290 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This double-blinded, randomised controlled trial (RCT) aims to determine the feasibility, tolerability, and safety of intermittent theta burst stimulation (iTBS) and oral ketamine (OK) as a comination treatment for post-traumatic stress disorder (PTSD). In this 10-week trial, participants will undergo 6 weeks of active treatment followed by 2 follow-up assessments.

Participants will be randomly assigned to one of two study arms:
1.) TMS-OK group: Participants will receive TMS five days a week over a 6-week period (30 TMS treatments total). Participants will receive a sub-anaesthetic dose of oral ketamine (OK) once a week over a 6-week period in a fixed dose of 1 mg/kg of body weight (6 ketamine treatments in total).

2.) TMS-sham + OK group: Participants will receive a sham course of TMS five days a week over a 6-week period (30 sham treatments in total). Participants will receive a sub-anaesthetic dose of oral ketamine (OK) once a week over a 6-week period in fixed dose of 1 mg/kg of body weight (6 ketamine treatments in total).

Dosing for Treatment Arm: Oral Ketamine and TMS
Oral Ketamine: Participants will receive a sub-anaesthetic dose of oral ketamine (OK) once a week over a 6-week period in fixed dose of 1 mg/kg of body weight (6 ketamine treatments in total).

TMS: We will deliver iTBS to the location of the left DLPFC at the intensity of 80% of resting motor with total 20 of 2 second train. Each train will include 10 high frequency bursts (each burst containing 3 pulses at 50Hz) delivering at 5.0 bursts per second (5Hz) for a total of 2 seconds.

Both TMS and TMS-sham will be administered on-site by trained research staff (psychiatrist, mental health nurse, registered nurse, research assistants). Each session will take between 20-30 minutes, including set-up, safety check, and treatment. Adherence will be recorded in the source documentation. If a participant is unable to attend or misses a TMS or TMS-sham treatment, they have the opportunity to make up a maximum of 5 sessions.

Oral ketamine will be administered on-site by the psychiatrist as per the dosage protocol on routine basis but can be administered by the MHNP as directed by the psychiatrist. The participants will be observed at Thompson Institute for up to two hours after the drug administration. An accountability logbook and controlled drug register (as per Queensland Governmental regulations) for ketamine will be maintained throughout the trial. If a participant is unable to attend or misses a ketamine treatment, details of the deviation will be recorded in the source documentation. Participants will be withdrawn from the study if they miss more than 2 ketamine treatments.
Intervention code [1] 318111 0
Treatment: Drugs
Intervention code [2] 318112 0
Treatment: Devices
Comparator / control treatment
Comparator arm: TMS-sham + OK group
Participants will receive a sham course of TMS five days a week over a 6-week period (30 sham treatments in total). Participants will receive a sub-anaesthetic dose of oral ketamine (OK) once a week over a 6-week period in a stable dose of 1.0mg per kilogram (6 ketamine treatments in total) through out the 6 weeks of active treatment.

Dosing for Comparator Arm: Oral Ketamine and sham TMS
Oral Ketamine: Participants will receive a sub-anaesthetic dose of oral ketamine (OK) once a week over a 6-week period in a stable dose of 1.0mg per kilogram (6 ketamine treatments in total) through out the 6 weeks of active treatment.

TMS sham condition: The MagPro Coil Cool-B65 A/P’s sham setting produces low-level current stimulation (less than 10% of electrical output produced in active TMS) to create skin sensations and auditory clicks replicating the auditory and tactile stimuli experienced by participants receiving active TMS. Max initial dB/ dt (near the coil surface), 36kT/s, Participants in the sham control will receive a sub-therapeutic dose, less than than 1% of active stimulation).
Control group
Placebo

Outcomes
Primary outcome [1] 324475 0
PTSD symptomology, as assessed by the PCL-5 between Baseline and Follow-up 1
Timepoint [1] 324475 0
The PCL-5 will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• 24-hours after ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment) (primary endpoint)

Secondary outcome [1] 384767 0
PTSD symptomology, as determined by the PCL-5 between Follow-up 1 and Follow-up 2

Timepoint [1] 384767 0
The PCL-5 will be administered at the following time points:
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-up 2 (4 weeks after final ketamine treatment)
Secondary outcome [2] 390321 0
Clinical side effects, assessed using psychiatric safety scales: Clinician-Administered Dissociative States Scale (CADSS), Brief Psychiatric Rating Scale (BPRS), and Young Mania Rating Scale (YMRS).

This is a composite secondary outcome.
Timepoint [2] 390321 0
The CADSS, BPRS, YMRS will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes after receiving ketamine treatment
• 24-hours after ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-up 2 (4 week after final ketamine treatment)
Secondary outcome [3] 390322 0
Clinically rated suicidality as assessed by the Beck Scale for Suicide Ideation (BSS).
Timepoint [3] 390322 0
The BSS will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-up 2 (4 weeks after final ketamine treatment)
Secondary outcome [4] 390323 0
Social and occupational functioning as assessed by Social and Occupational Assessment Scale (SOFAS).
Timepoint [4] 390323 0
SOFAS will be administered at the following time points:
• Baseline (week 0)
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-up 2 (4 weeks after final ketamine treatment)
Secondary outcome [5] 390324 0
Perceived pleasure as assessed by the Snaith Hamilton Pleasure Scale (SHAPS-C).
Timepoint [5] 390324 0
The SHAPS-C will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [6] 390325 0
Depression, as assessed by the Montgomery – Asberg Depression Rating Scale (MADRS).
Timepoint [6] 390325 0
The MADRS will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [7] 390326 0
Depression, assessed using the Depression subscale of the Depression, Anxiety and Stress Scale (DASS-21).
Timepoint [7] 390326 0
The DASS-21 will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• 24 hours post-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [8] 390327 0
Anxiety, assessed by anxiety subscale of the Depression, Anxiety and Stress Scale (DASS-21)
Timepoint [8] 390327 0
The DASS-21 will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• 24 hours post-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [9] 390328 0
Self-rated stress, assessed through the stress subscale of the Depression, Anxiety and Stress Scale (DASS-21)
Timepoint [9] 390328 0
The DASS-21 will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• 24 hours post-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [10] 390329 0
Self-rated stress, assessed through the use of the Perceived Stress Scale (PSS).
Timepoint [10] 390329 0
The PSS will be administered at the following time points:
• Baseline (week 0)
• 24 hours after week 3 of ketamine treatment
• 24 hours after week 6 of ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [11] 390330 0
Global wellbeing, assessed using the World Health Organization Wellbeing Index (WHO-5).
Timepoint [11] 390330 0
The WHO-5 will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [12] 390331 0
Sleep quality, assessed using the Pittsburgh Sleep Quality Index Addendum for PTSD (PSQI-A)
Timepoint [12] 390331 0
The PSQI-A will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [13] 390341 0
Neurobiology as an outcome of ketamine treatment will be assessed by magnetic resonance imaging (MRI) at 5 timepoints.
Timepoint [13] 390341 0
MRI will be conducted at 5 time points:
• Baseline (week 0)
• 24 hours after week 3 of ketamine treatment
• 24 hours after week 6 of ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine
Secondary outcome [14] 390343 0
Electroencephalography (EEG) will be used to assess changes in neural network communication from BAS to FUP1 and FUP2
Timepoint [14] 390343 0
EEG will be administered at the following time points:
• Baseline (week 0)
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [15] 390344 0
Cambridge Neuropsychological Test Automated Battery (CANTAB) will be used to assess cognitive functioning such as attention, working memory, speed of processing, and executive functioning.
Timepoint [15] 390344 0
The computerized cognitive battery will be administered at the following time points:
• Baseline (week 0)
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-Up 2 (4 weeks after final ketamine treatment)
Secondary outcome [16] 391513 0
PTSD diagnosis, as assessed using the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) from FUP1 to FUP2.
Timepoint [16] 391513 0
Clinician Administered PTSD Scale for DSM-5 (CAPS-5) will be administered at the following time points:
• Follow-up 1 (1 week after final ketamine treatment).
• Follow-up 2 (4 weeks after final ketamine treatment).
Secondary outcome [17] 391769 0
Clinical side effects, assessed using the symptom tolerability scale: Frequency, Intensity, Burden of Side Effects Rating (FIBSER).
Timepoint [17] 391769 0
The FIBSER will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes after receiving ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-up 2 (4 week after final ketamine treatment)
Secondary outcome [18] 391770 0
Clinical side effects, assessed using the symptom tolerability scale: Patient Rated Inventory of Side Effects (PRISE).
Timepoint [18] 391770 0
The PRISE will be administered at the following time points:
• Baseline (week 0)
• 30-60 minutes pre-ketamine treatment
• 24-hours after ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-up 2 (4 week after final ketamine treatment)
Secondary outcome [19] 391771 0
PTSD diagnosis, as assessed using the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) between BAS and FUP1.
Timepoint [19] 391771 0
The (CAPS-5) will be administered at the following time points:
• Baseline (week 0)
• Follow-up 1 (1 week after final ketamine treatment)
Secondary outcome [20] 391772 0
PTSD diagnosis, as assessed using the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) between BAS and FUP2.
Timepoint [20] 391772 0
The (CAPS-5) will be administered at the following time points:
• Baseline (week 0)
• Follow-up 2 (4 weeks after final ketamine treatment)
Secondary outcome [21] 391773 0
PTSD diagnosis, as assessed using the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) between FUP1 and FUP2.
Timepoint [21] 391773 0
The (CAPS-5) will be administered at the following time points:
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-up 2 (4 weeks after final ketamine treatment)

Eligibility
Key inclusion criteria
•Current PTSD diagnosis
•Persons (male/female/other) aged over 18 years
•Participants must be able to understand and provide consent on the Participant Information and Consent Form (PICF).
•Participants must be able to tolerate the ketamine treatment, TMS treatment/sham TMS treatment, rating scales, blood testing and urinalysis in order to remain in the study and this will be monitored on an ongoing basis, as per the methodology.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Psychiatric conditions:
•Psychosis
•Mania/hypomania
•Acute suicidality requiring urgent psychiatric intervention
•History of ketamine use disorder
•History of epilepsy/seizures

Physical conditions:
•Participants who have active or inactive implants (including device leads), including deep brain stimulators, cochlear implants, and vagus nerve stimulators.
•The presence of ferrous metal pins or plates in or near the head (within 30 cm of the coil). Including: implanted electrodes/stimulators, aneurysm clips or coils, stents, or bullet fragments.
•Participants who have history of epilepsy or unexplained seizure history.
•Participants who have previously undergone TMS treatment.
•Uncontrolled/severe symptomatic cardiovascular disease states including: recent myocardial infarction (within prior 6 months); history of stroke; and hypertension (resting blood pressure >150/100)
•Body weight of >130kg
•History of intracranial mass, intracranial haemorrhage/stroke, cerebral trauma/traumatic brain injury or increased intracranial pressure (as assessed by referring general practitioner)
•Liver function test (LFT) results out of normal range, as specified below:
•ALT: >135 U/L
•AST: >123 U/
•GAMMA GT (GGT) male participants: >210 U/L
•GAMMA GT (GGT) – female participants: >135 U/L
•TOTAL BILIRUBIN (BIT): >60 umol/L
•ALBUMIN (A): <25g/L and >150g/L
•ALK PHOS (ALP): >345 U/L
•Previous reaction to ketamine (as reported by referring general practitioner and participant)
•Participants who have undergone TMS treatment previously
•Participants who are pregnant, currently breastfeeding, or who are planning a pregnancy during the trial
•Participants who are simultaneously engaging in another clinical intervention trial while participating in TMS-OK PTSD.
•Participants with a history of substance use disorder (excluding ketamine use disorder), may be eligible to participate in the study if they abstain from use of the substance two weeks prior to participation in the trial and for the remainder of the 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)
the MagPro Coil Cool-B65 A/P will be programmed to conceal allocation
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
To generate the TMS sham condition, the MagPro Coil Cool-B65 A/P will be utilised to ensure effective double-blinding. The MagPro TMS machine will be programmed to randomise participant ID’s with a 1:1 active-to-sham treatment ratio. Participant and TMS operator ID codes will be managed by MagPro’s randomisation software ensuring that neither study investigators nor participants have access to blinded information.
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
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The sample size (N = 100) for this study was determined by the value where increasing sample size will not appreciably decrease the effect size for a two-tailed two independent samples t-test. The sample size of 100 patients ensures that mean difference of 0.65 standard deviations (medium to large effect according to the Cohen effect size convention1) for any measures will be detected with type I error rate of 0.05 and power of 80%.

1. Cohen J. Statistical power analysis for the behavioural sciences. New York: Academic Press; 1969.


Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD

Funding & Sponsors
Funding source category [1] 306230 0
University
Name [1] 306230 0
Thompson Institute, University of the Sunshine Coast
Address [1] 306230 0
12 Innovation Parkway, Birtinya, QLD, 4575
Country [1] 306230 0
Australia
Primary sponsor type
University
Name
Thompson Institute, University of the Sunshine Coast
Address
12 Innovation Parkway, Birtinya, QLD, 4575
Country
Australia
Secondary sponsor category [1] 306711 0
None
Name [1] 306711 0
NA
Address [1] 306711 0
NA
Country [1] 306711 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306441 0
Bellberry Limited
Ethics committee address [1] 306441 0
123 Glen Osmond Road,
Eastwood SA 5063
Ethics committee country [1] 306441 0
Australia
Date submitted for ethics approval [1] 306441 0
22/12/2020
Approval date [1] 306441 0
24/03/2021
Ethics approval number [1] 306441 0
2020-07-653

Summary
Brief summary
This double-blinded, randomised controlled trial aims to determine the feasibility, tolerability, and safety of intermittent theta burst stimulation (iTBS) and oral ketamine (OK) as a combination treatment for PTSD. Given the complexity and broad range of symptom presentations in patients diagnosed with PTSD, this study seeks to capture changes in sleep quality, perceived stress, suicidality, depression, anhedonia, chronic pain, and social/occupational functioning. Findings from this study will help to identify the brain circuitry involved with and neural processes associated with these glutamatergic and GABAergic-based interventions.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 103886 0
Dr Adem Can
Address 103886 0
Thompson Institute, University of the Sunshine Coast
12 Innovation Parkway, Birtinya, QLD, 4575
Country 103886 0
Australia
Phone 103886 0
+61 07 5456 5385
Fax 103886 0
Email 103886 0
acan@usc.edu.au
Contact person for public queries
Name 103887 0
Ms Cyrana Gallay, MSc
Address 103887 0
Thompson Institute, University of the Sunshine Coast
12 Innovation Parkway, Birtinya, QLD, 4575
Country 103887 0
Australia
Phone 103887 0
+61 07 5456 5386
Fax 103887 0
Email 103887 0
TI_ClinicalResearch@usc.edu.au
Contact person for scientific queries
Name 103888 0
Ms Cyrana Gallay, MSc
Address 103888 0
Thompson Institute, University of the Sunshine Coast
12 Innovation Parkway, Birtinya, QLD, 4575
Country 103888 0
Australia
Phone 103888 0
+61 7 5456 5386
Fax 103888 0
Email 103888 0
cgallay@usc.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
No other documents available
Summary results
No Results