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Trial registered on ANZCTR


Registration number
ACTRN12618001937202
Ethics application status
Approved
Date submitted
22/11/2018
Date registered
29/11/2018
Date last updated
26/07/2019
Date data sharing statement initially provided
29/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Extended and Maintenance Oral Ketamine Trial on Suicidality
Scientific title
A longitudinal open-label, dose-ranging clinical trial to evaluate the effectiveness of oral ketamine, an NMDA (N-methyl-D-aspartate) receptor antagonist, in patients who are experiencing chronic suicidal ideation.
Secondary ID [1] 296677 0
CT-2018-CTN-04141-1
Universal Trial Number (UTN)
Trial acronym
OKTOS-E and OKTOS-M
Linked study record
OKTOS: ACTRN12618001412224

Health condition
Health condition(s) or problem(s) studied:
Chronic suicidality 310521 0
Condition category
Condition code
Mental Health 309233 309233 0 0
Suicide

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants who completed the original OKTOS pilot study and who are deemed eligible based on clinical parameters will be invited to participate in the two-phase extension study.
The extension study will involve delivery of oral ketamine over a 12-week period (maximum) for Phase 1 (OKTOS-E) and over 26 weeks (maximum) for Phase 2 (OKTOS-M). The same participants will be involved in both phases of the trial. There may be a break of up to 10 days between commencement of Phase 2 to allow for completion of MRI and EEG data collection at the end of Phase 1 (MRI and EEG to be conducted within +1 – 10 days of final treatment). Completion of MRI and EEG data at the end of Phase 2 may occur between +1 – 10 days of final treatment.

During both study phases, participants will be administered a sub-anaesthetic dose of oral ketamine on treatment days. The ketamine will be administered as an oral liquid formulation, in a dose ranging between 0.5 - 3.0 mg/kg. The ketamine will be administered by the psychiatrist, or the Mental Health Nurse Practitioner (under the direction of the psychiatrist).

The dose administered at each treatment timepoint during OKTOS-E and OKTOS-M will be the dose found to be most tolerable for the individual participant during their participation in OKTOS.

There will be one to four weeks between each treatment day, depending on individual participant’s clinical needs. The first interval between treatments will be two weeks. OKTOS-E (phase 1) participants will be administered between 4 - 11 doses of ketamine during this phase. OKTOS-M (phase 2) participants will be administered between 7 - 26 doses of ketamine during this phase.

To improve intervention fidelity, ketamine is administered as a liquid and consumed in front of clinicians, with onsite monitoring immediately post-consumption of the treatment. Participants will be given treatment appointment times and reminders in advance and will have contact with nursing staff in between treatments. To further increase treatment adherence, participants are provided ongoing psychoeducation regarding the intervention and likely transient side-effects.
Intervention code [1] 312990 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 308202 0
Our primary aim is to examine the longitudinal effectiveness of oral ketamine, an NMDA (N-methyl-D-aspartate) receptor antagonist, in patients who are experiencing chronic suicidal ideation.

Change in suicidality will be assessed using the Beck Scale for Suicide Ideation (BSS) and the Suicidal Ideation Attributes Scales (SIDAS) as a composite outcome.
Timepoint [1] 308202 0
The BSS and SIDAS rating scales will be used immediately prior to and immediately after each treatment, as well as during follow-up phone calls and at the study-end. Treatments will occur every one to four weeks. Follow-up phone calls will occur at +4 or 5
days post-treatment.
Secondary outcome [1] 354225 0
This study aims to further understand the neuropathology of suicidality. MRI will be used to examine changes in resting state, brain structure, and the glutamatergic system as an exploratory outcome.
Timepoint [1] 354225 0
This neurological measure will be conducted at the end-of-study visit for both phases of the extension study.
Secondary outcome [2] 354226 0
To examine and explore the tolerability and safety of longitudinal treatment with oral ketamine, an NMDA (N-methyl-D-aspartate) receptor antagonist, in patients who are experiencing chronic suicidal ideation.
There is risk of physical side effects associated with ketamine use, including:
- increased/decreased blood pressure and pulse rate,
- nausea and vomiting,
- temporary light-headedness, headache, diplopia, drowsiness, dizziness, and
- ketamine-induced urinary cystitis.
There is potential for temporary adverse psychiatric effects, including:
- experiencing flashbacks,
- anxiety,
- anxiety-depression,
- spacey feelings/fogginess in head,
- sleepiness,
- disengagement,
- thought disorder,
- withdrawal,
- retardation,
- hostility-suspiciousness,
- anger,
- sadness, and
- irritability.

There is risk of female participants becoming pregnant during the trial period and risk of male participants fathering children during the trial period.

Tolerability and safety will be examined by assessing participant's vital signs, conducting urinalysis, and using rating scales to assess dissociation and mania, bladder and urinary symptoms, and general side effects.
Rating scales to be used for safety monitoring are:
- Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS)
- Clinician Administered Dissociative States Scale (CADSS)
- Brief Psychiatric Rating Scale (BPRS)
- Young Mania Rating Scale (YMRS)
- Patient Rated Inventory of Side Effects (PRISE)
- Frequency, Intensity, and Burden of Side Effects Rating Scale (FIBSER)
Timepoint [2] 354226 0
Urinalysis will be conducted immediately prior to each treatment. Vital signs will be assessed on treatment days - once prior to each treatment and at 30mins and 60mins post-treatment. Rating scales will be used prior to and after each treatment, during follow-up phone calls (+4 or 5 days post-treatment), and at the end-of-study visit for both phases.
Female participants of childbearing age will have pregnancy tested via urine test prior to their first treatment with ketamine. Urine pregnancy tests will be conducted at least monthly for female participants of childbearing age, but more frequently if required. As there is no available data about the safety in humans of ongoing oral ketamine on spermatogenesis, sperm quality and safety with respect to potential offspring, we will ask male participants to abstain from fathering a child by using highly effective birth control methods (i.e. resulting in a low failure rate [less than 1% per year) in order to minimise and/or prevent any risk of unintentional exposure of the embryo/foetus to potentially harmful effect of ketamine during the treatment phase and for 5 terminal plasma half-lives plus 74 days (one human spermatogenesis cycle) post-treatment.
Secondary outcome [3] 354227 0
This study aims to examine changes in brain-derived neurotrophic factor levels following longitudinal ketamine treatment. BDNF will be examined using serum Enzyme-Linked Immunosorbent Assay (ELISA).
Timepoint [3] 354227 0
Blood for serum BDNF analysis will be drawn at the end of phase 1 (OKTOS-E: 12 weeks) and at the end of phase 2 (OKTOS-M: 26 weeks).
Secondary outcome [4] 354431 0
This study aims to examine changes in participant’s cholesterol levels following longitudinal ketamine treatment. Cholesterol will be examined using blood samples with standard pathology testing.
Timepoint [4] 354431 0
At the end of phase 1 (OKTOS-E: 12 weeks) and at the end of phase 2 (OKTOS-M: 26 weeks).
Secondary outcome [5] 354458 0
This study aims to further understand the neuropathology of suicidality. EEG will be used to explore electrophysiological changes.
Timepoint [5] 354458 0
This neurological measure will be conducted at the end-of-study visit for both phases of the extension study.
Secondary outcome [6] 354459 0
This study aims to understand changes overall functioning of participants receiving oral ketamine longitudinally. Functioning will be assessed using the Who-5 Well-Being Index (WHO-5) and the Social and Occupational Functioning Assessment Scale (SOFAS) rating scales.
Timepoint [6] 354459 0
These scales will be used at the end-of-study visits for both phases of the extension study. Results will be compared to those collected in the original OKTOS pilot study.
Secondary outcome [7] 354460 0
This study aims to understand changes in the mental state of participants receiving oral ketamine longitudinally. Participant's mental state will be assessed using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Depression, Anxiety and Stress Scale – 21 Items (DASS-21).
Timepoint [7] 354460 0
The MADRS will be used on treatment days, prior to the administration of oral ketamine and at the end-of-study visit for both phases of the extension study.
The DASS-21 will be used on treatment days, prior to the administration of oral ketamine and 60 minutes after the administration of oral ketamine, and at the end-of-study visit for both phases of the extension study.

Eligibility
Key inclusion criteria
Participant Inclusion Criteria for OKTOS-E (Phase 1):
• Participants must have previously completed the Oral Ketamine Trial on Suicidality (OKTOS) (Bellberry Limited Application ID 2017-12-982) including the four-week follow-up phase.
• Participant continues to receive a score equal to or above 6 for the Scale for Suicidal Ideation (SSI) at the completion of OKTOS OR participant receives a score >6 for the Scale for Suicidal Ideation (SSI) at any time within 12 weeks of completing OKTOS.
• Persons (male/female/other) aged over 18 years.
• Participant to receive physical examination from Principal Investigator within 14 days prior to commencement of ketamine treatment to eliminate possibility of conditions outlined in exclusion criteria.
• Participants must be able to understand the PIF and provide written informed consent on the Participant Consent Form (PCF).
• Total avoidance of pregnancy for the duration of the study through abstinence or adequate and highly effective contraception (i.e. methods resulting in a low failure rate [less than 1% per year]) and/or the inability to become pregnant through age or surgical sterilization.
• Male participants must avoid fathering a child during the study and for 3 months following the final ketamine treatment.



Participant Inclusion Criteria for OKTOS-M (Phase 2):
• Participants must have previously completed the Oral Ketamine Trial on Suicidality (OKTOS) (Bellberry Limited Application ID 2017-12-982) and the Extended Oral Ketamine Trial on Suicidality (OKTOS-E).
• Persons (male/female/other) aged over 18 years.
• Participant to receive physical examination from Principal Investigator within 14 days prior to commencement of ketamine treatment to eliminate possibility of conditions outlined in exclusion criteria.
• Participants must be able to understand the PIF and provide written informed consent on the Participant Consent Form (PCF).
• Total avoidance of pregnancy for the duration of the study through abstinence or adequate and highly effective contraception (i.e. methods resulting in a low failure rate [less than 1% per year]) and/or the inability to become pregnant through age or surgical sterilization.
• Male participants must avoid fathering a child during the study and for 3 months following the final ketamine treatment.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Persons under 18 years of age
• Psychosis
• Mania/hypomania
• Acute suicidality requiring urgent psychiatric intervention
• Uncontrolled/severe symptomatic cardiovascular disease states including: recent myocardial infarction (within prior 6 months); history of stroke; and hypertension (resting blood pressure >150/100)
• 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)
• Pregnant women
• Breastfeeding women
• Experiencing any adverse event/s (AEs) during OKTOS or OKTOS-E
• Experiencing any unexpected adverse reaction/s (UARs) during OKTOS or OKTOS-E
• Experiencing any serious adverse event/s (SAEs) during OKTOS or OKTOS-E
• Experiencing any known but intolerable side effects during OKTOS or OKTOS-E

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
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] 301256 0
University
Name [1] 301256 0
Sunshine Coast Mind and Neuroscience - Thompson Institute, University of the Sunshine Coast
Address [1] 301256 0
12 Innovation Parkway, Birtinya QLD 4575
Country [1] 301256 0
Australia
Primary sponsor type
University
Name
Sunshine Coast Mind and Neuroscience - Thompson Institute, University of the Sunshine Coast
Address
12 Innovation Parkway, Birtinya QLD 4575
Country
Australia
Secondary sponsor category [1] 300896 0
None
Name [1] 300896 0
Address [1] 300896 0
Country [1] 300896 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301997 0
Bellberry Limited
Ethics committee address [1] 301997 0
129 Glen Osmond Road, Eastwood, South Australia 5063
Ethics committee country [1] 301997 0
Australia
Date submitted for ethics approval [1] 301997 0
14/09/2018
Approval date [1] 301997 0
26/11/2018
Ethics approval number [1] 301997 0
2018-09-768

Summary
Brief summary
This longitudinal study is an extension of the Oral Ketamine Trial on Suicidality. This study is an open-label, dose-ranging clinical trial of oral ketamine.

Treatment will involve administration of oral ketamine over a 12-week period for Phase 1 (OKTOS-E) and over 26 weeks for Phase 2 (OKTOS-M).

The pathology and neurobiology of suicidality will be examined via MRI and EEG as neurological measures. The primary outcome of change in suicidality will be assessed using the Beck Scale for Suicide Ideation (BSS) and the Suicidal Ideation Attributes Scales (SIDAS) as a composite outcome
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 88802 0
Dr Adem Can
Address 88802 0
Sunshine Coast Mind and Neuroscience - Thompson Institute
12 Innovation Parkway, Birtinya QLD 4575
Country 88802 0
Australia
Phone 88802 0
+61 7 54301191
Fax 88802 0
Email 88802 0
Adem.Can@research.edu.au
Contact person for public queries
Name 88803 0
Dr Adem Can
Address 88803 0
Sunshine Coast Mind and Neuroscience - Thompson Institute
12 Innovation Parkway, Birtinya QLD 4575
Country 88803 0
Australia
Phone 88803 0
+61 7 54301191
Fax 88803 0
Email 88803 0
Adem.Can@research.edu.au
Contact person for scientific queries
Name 88804 0
Dr Adem Can
Address 88804 0
Sunshine Coast Mind and Neuroscience - Thompson Institute
12 Innovation Parkway, Birtinya QLD 4575
Country 88804 0
Australia
Phone 88804 0
+61 7 54301191
Fax 88804 0
Email 88804 0
Adem.Can@research.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
No - IPD will not be available. Our trial has a relatively small number of participants and is conducted in a localized region. There is a risk of data being identifiable if publicly shared.
What supporting documents are/will be available?
No other documents available
Summary results
No Results