Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001965291
Ethics application status
Approved
Date submitted
21/11/2018
Date registered
5/12/2018
Date last updated
21/05/2024
Date data sharing statement initially provided
5/12/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Oral Ketamine Trial on Post-Traumatic Stress Disorder
Scientific title
An open-label, dose ranging, clinical trial of oral ketamine, an NMDA (N-methyl-D-aspartate) receptor antagonist, with weekly dosing over six weeks in patients who are experiencing post-traumatic stress disorder (PTSD)
Secondary ID [1] 296523 0
CTN ID: CT-2018-CTN-03765-1 v1, Protocol: AU/1/7867310.
Universal Trial Number (UTN)
U1111-1224-3868
Trial acronym
OKTOP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Post-traumatic stress disorder 310305 0
Condition category
Condition code
Mental Health 309038 309038 0 0
Other mental health disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This trial aims to determine the feasibility, tolerability, and safety of oral ketamine (OK) as a 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 administered a sub-anaesthetic oral dose of ketamine once a week for a period of 6 weeks. The initial dose will be 0.5mg per kilogram, after which dose amounts will be increased by between 0.1mg and 1mg/kg in each treatment, with a maximum dose of 3.0mg/kg. Upon reaching 3.0mg/kg, participants will continue at that level until the end of the treatment phase, provided they tolerate the dose, i.e. “endure the action of ketamine without any side effect or discomfort”.

Oral ketamine will be administered on-site by the psychiatrist as per the dosage protocol on routine basis but can be administered by the Mental Health Nurse Practitioner (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] 312834 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 307998 0
PTSD symptomology, as assessed by the PTSD Checklist for DSM-5 (PCL-5) between baseline (BAS) and Follow-up 1.
Timepoint [1] 307998 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)
• Follow-up 2 (4 weeks after final ketamine treatment)
Secondary outcome [1] 353617 0
Change in PTSD symptomology, as determined by the PCL-5 between FUP1 and FUP2
Timepoint [1] 353617 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] 353618 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] 353618 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] 406299 0
Clinically rated suicidality as assessed by the Beck Scale for Suicide Ideation (BSS).
Timepoint [3] 406299 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] 406300 0
Social and occupational functioning as assessed by Social and Occupational Assessment Scale (SOFAS).
Timepoint [4] 406300 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] 406301 0
Perceived pleasure as assessed by the Snaith Hamilton Pleasure Scale (SHAPS-C).
Timepoint [5] 406301 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] 406302 0
Depression, as assessed by the Montgomery – Asberg Depression Rating Scale (MADRS).
Timepoint [6] 406302 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] 406303 0
Depression, assessed using the Depression subscale of the Depression, Anxiety and Stress Scale (DASS-21).
Timepoint [7] 406303 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] 406304 0
Self-rated stress, assessed through the use of the Perceived Stress Scale (PSS).
Timepoint [8] 406304 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 [9] 406305 0
Global wellbeing, assessed using the World Health Organization Wellbeing Index (WHO-5).
Timepoint [9] 406305 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 [10] 406306 0
Sleep quality, assessed using the Pittsburgh Sleep Quality Index Addendum for PTSD (PSQI-A)
Timepoint [10] 406306 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 [11] 406307 0
The relationship between glutamate and brain-derived neurotrophic factor (BDNF) will be assessed via research blood tests across 5 timepoints.
Timepoint [11] 406307 0
Research blood tests 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 [12] 406308 0
MRI will be utilized to examine a variety of neurobiological changes, including neuroanatomical changes in density, volume, and white matter tract connectivity
Timepoint [12] 406308 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 [13] 406309 0
Electroencephalography (EEG) will be used to assess changes in neural network communication from BAS to FUP1 and FUP2.
Timepoint [13] 406309 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 [14] 406310 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 [14] 406310 0
The computerised 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 [15] 406311 0
PTSD diagnosis, as assessed using the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) between Baseline (Week 0) and Follow-up 1 (FUP1).
Timepoint [15] 406311 0
Clinician Administered PTSD Scale for DSM-5 (CAPS-5) will be administered at the following time points:
• Baseline (week 0)
• Follow-up 1 (1 week after final ketamine treatment).
Secondary outcome [16] 406312 0
PTSD diagnosis, as assessed using the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) between Baseline (Week 0) and Follow-up 2 (FUP2).
Timepoint [16] 406312 0
Clinician Administered PTSD Scale for DSM-5 (CAPS-5) will be administered at the following time points:
• Baseline (week 0)
• Follow-up 2 (4 weeks after final ketamine treatment).
Secondary outcome [17] 406313 0
PTSD diagnosis, as assessed using the Clinician Administered PTSD Scale for DSM-5 (CAPS-5) between Follow-up 1 and Follow-up 2.
Timepoint [17] 406313 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 [18] 406314 0
Clinical side effects, assessed using the symptom tolerability scale: Frequency, Intensity, Burden of Side Effects Rating (FIBSER).
Timepoint [18] 406314 0
The FIBSER will be administered at the following time points:
• Baseline (week 0)
• 24 hours post-ketamine treatment
• Follow-up 1 (1 week after final ketamine treatment)
• Follow-up 2 (4 week after final ketamine treatment)
Secondary outcome [19] 406315 0
Clinical side effects, assessed using the symptom tolerability scale: Patient Rated Inventory of Side Effects (PRISE).
Timepoint [19] 406315 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 [20] 406316 0
Anxiety, assessed using the Anxiety subscale of the Depression, Anxiety and Stress Scale (DASS-21).
Timepoint [20] 406316 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 [21] 406317 0
Self-rated stress, assessed through the stress subscale of the Depression, Anxiety and Stress Scale (DASS-21).
Timepoint [21] 406317 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)

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, 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
Sex
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

Physical conditions:
•Participants who have history of epilepsy or unexplained seizure history.
•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 >150kg
•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 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 OKTOP
•Participants with a history of substance use disorder (excluding ketamine use disorder), may be eligible to participate in the study if they abstain from alcohol or illicit substance use 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
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Statistical Analyses will include generalised linear models (GLMs), analysis of the relative change index, Frequentist statistics, and Bayesian statistics. A significance level of .05 will be utilized where required. Data will be inspected for outliers and any spurious data will be corrected or removed prior to analysis.

Recruitment
Recruitment status
Suspended
Date of first participant enrolment
Anticipated
11/02/2021
Actual
8/07/2021
Date of last participant enrolment
Anticipated
28/02/2025
Actual
26/10/2023
Date of last data collection
Anticipated
1/05/2025
Actual
Sample size
Target
50
Accrual to date
40
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment postcode(s) [1] 24625 0
4575 - Birtinya

Funding & Sponsors
Funding source category [1] 301108 0
University
Name [1] 301108 0
University of the Sunshine Coast, Thompson Institute
Country [1] 301108 0
Australia
Primary sponsor type
University
Name
University of the Sunshine Coast Mind and Neuroscience Thompson Institute
Address
12 Innovation Parkway, Birtinya, Queensland, 4575
Country
Australia
Secondary sponsor category [1] 300719 0
None
Name [1] 300719 0
Address [1] 300719 0
Country [1] 300719 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301858 0
Prince Charles Hospital Human Research Ethics Committee
Ethics committee address [1] 301858 0
Building 14
Rode Road
CHERMSIDE QLD 4032
Ethics committee country [1] 301858 0
Australia
Date submitted for ethics approval [1] 301858 0
27/07/2018
Approval date [1] 301858 0
06/09/2018
Ethics approval number [1] 301858 0
Project ID: 42836. HREC/18/QPCH/288:

Summary
Brief summary
This open-label, dose-ranging clinical trial which aims to determine the feasibility, tolerability, and safety of oral ketamine (OK) for post-traumatic stress disorder. In this 10-week trial, participants will undergo 6 weeks of active treatment followed by 2 follow-up assessments (week 7; week 10)

Participants (N = 50) will be receive a sub-anaesthetic dose of OK once a week over a 6-week period (according to an established titration protocol; 6 ketamine treatments in total);

• All participants will be engaged with their treating doctors for the duration of the trial.
• Ketamine will be used as an adjunctive treatment, meaning that participants are able to maintain or modify their current treatments under guidance of their physician. Any changes to medication will be recorded by study staff.

Primary hypothesis: That a 6-week OK treatment will be efficacious in reducing PTSD symptom frequency and severity.

Secondary hypotheses: That a 6-week OK treatment will be efficacious in: reducing stress, anxiety, depression, suicidal ideation; Improving cognitive, social, and occupational functioning; Improving sleep quality; Improving overall wellbeing.

Additionally, this study aims to examine the cognitive, neurobiological, and neurophysiological effects of OK treatment in adult participants with PTSD.

All changes outlined in this ANZCTR have been approved prior by Princes Charles Hospital Human Research Ethics Committee.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88342 0
Dr Adem Can
Address 88342 0
University of the Sunshine Coast Thompson Institute 12 Innovation Parkway, Birtinya QLD, 4575
Country 88342 0
Australia
Phone 88342 0
+61 7 5430 1285
Fax 88342 0
Email 88342 0
[email protected]
Contact person for public queries
Name 88343 0
Trish Wilson
Address 88343 0
University of the Sunshine Coast Thompson Institute 12 Innovation Parkway, Birtinya QLD, 4575
Country 88343 0
Australia
Phone 88343 0
+61 075456 3893
Fax 88343 0
Email 88343 0
[email protected]
Contact person for scientific queries
Name 88344 0
Dr Adem Can
Address 88344 0
University of the Sunshine Coast Mind and Neuroscience Thompson Institute
12 Innovation Parkway, Birtinya QLD, 4575
Country 88344 0
Australia
Phone 88344 0
+61 07 5456 3893
Fax 88344 0
Email 88344 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


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.