Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001592437
Ethics application status
Approved
Date submitted
15/11/2016
Date registered
18/11/2016
Date last updated
1/12/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Single dose ketamine pharmacokinetic-pharmacodynamic relationships in healthy volunteers
Scientific title
Single dose ketamine pharmacokinetic-pharmacodynamic relationships in healthy volunteers
Secondary ID [1] 290521 0
nil known
Universal Trial Number (UTN)
Trial acronym
Early Ketamine PK-PD
Linked study record

Health condition
Health condition(s) or problem(s) studied:
major depressive disorder 300931 0
post traumatic stress disorder 300934 0
obsessive compulsive disorder 300935 0
generalized anxiety disorder 300936 0
social phobia 300937 0
Condition category
Condition code
Mental Health 300737 300737 0 0
Depression
Mental Health 300804 300804 0 0
Anxiety

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Volunteers will receive a single subcutaneous injection (either saline placebo, or ketamine 0.5 or 1mg/kg).
Intervention code [1] 296370 0
Treatment: Drugs
Comparator / control treatment
saline placebo
Control group
Placebo

Outcomes
Primary outcome [1] 300151 0
ketamine pharmacokinetics
Parameters assessed Cmas, AUC, Tmax
Outcome assessed by plasma assay
Timepoint [1] 300151 0
timepoints are: pre-dose, 3, 6, 10, 15, 30, 45, 60, 90, 120 & 180 minutes & 24 hrs post-dose
Primary outcome [2] 300152 0
Brain-derived neurotrophic factor (BDNF) pharmacokinetics
Parameters assessed Cmas, AUC, Tmax
Outcome assessed by serum assay
Timepoint [2] 300152 0
timepoints are: pre-dose, 3, 6, 10, 15, 30, 45, 60, 90, 120 & 180 minutes and 24 hrs post-dose
Primary outcome [3] 300153 0
Cognitive testing
Tests:
- Self rated mood (happy, sad, calm, tense, energetic, and sleepy, rated from 0 (Not at all…) to 100 (Extremely…).
- Pro assesses basic visuomotor performance (a green square appears on the left or right and subjects have to press the key on the same side as the square). Anti assesses inhibitory control (a red square appears on the left or right and subjects have to press the key on the opposite side of the square). Pro/Anti assesses switching abilities (a green or red square appears on the left or right and subjects have to press the key on the same side as green squares and on the opposite side of red squares.
- Simon assesses the ability to ignore irrelevant spatial information (one of two possible consonants appear to the left or right of centre and subjects have to indicate the identity of the consonant by pressing the assigned left or right key; thus the position of the consonant is either congruent or incongruent with the side of the correct response).
- Flanker assesses the ability to ignore irrelevant identity-based information (one of two possible consonants appear at centre and one appears above or below centre; the two consonants are either the same (congruent) or different (incongruent) and subjects have to indicate the identity of the central consonant by pressing the assigned key, with the flanking consonant to be ignored),
- Forward Spatial assesses short-term memory capacity (a computerized version of the Corsi block tapping task) that involves viewing nine boxes that light up in a predetermined random sequence followed by a tone signalling the subject to indicate the sequence using a mouse to click on boxes; each sequence length occurs twice; if the subject responds correctly to at least one of the two occurrences, the program increases the length of the sequence by one box up to a maximum length of nine boxes
- Backward Spatial assesses short-term memory manipulation (identical to Forward Spatial except that the sequence has to be recalled in the reverse order; i e., click the boxes in the opposite order to which they lit up).
- The 2-back test assesses working memory (consonants, except for W, Y, and Z, appear one at a time centred on the screen in a predetermined random sequence; subjects indicate whether each consonant matches the consonant two-back in the sequence).


Timepoint [3] 300153 0
Timepoints are: pre-dose, 45 mins, 3 hours, and 24 hours post-dose
Secondary outcome [1] 329429 0
This is a primary outcome
EEG
10 minute relaxation EEG - subjects will alternate once a minute between eyes open and eyes closed
Timepoint [1] 329429 0
Timepoints are: pre-dose, 2hrs, 24hrs and 168 hrs post-dose

Eligibility
Key inclusion criteria
Capable of understanding and signing an informed consent
Aged > 18 years on the day of consent
Good general health
Suitable venous access
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Females who are or intend to become pregnant, or are lactating.
2. Participants who, in the opinion of the investigator, do not understand the information and procedures of the study, or would not be compliant with them (in particular the study restrictions and risks involved).
3. Any participant for whom the investigator believes, for any reason, that participation would not be an acceptable risk.
4. Current use of monoamine oxidase inhibitors (MAOIs), thyroxine or stimulants (amphetamine/methyphenidate)
5. Regular use of any drug that alters mood or is used to treat mental disorder, including daily use of alcohol or use of alcohol within 24 hours of testing.
6. Use of medications that may alter BDNF concentrations, including antidepressants
7. Subjects with a prior history of seizures; susceptibility to photosensitivity; or a history of allergic skin reactions.

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)
Prof Glue will create the random codes. All study personnel involved with recruitment, dosing, data collection and analysis will have no access to the random codes until the databases are locked.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated random code, with stratification based on gender
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 1
Type of endpoint/s
Pharmacokinetics / pharmacodynamics
Statistical methods / analysis

Recruitment
Recruitment status
Withdrawn
Reason for early stopping/withdrawal
Other reasons/comments
Other reasons
trial no longer necessary
Date of first participant enrolment
Anticipated
9/01/2017
Actual
Date of last participant enrolment
Anticipated
30/06/2017
Actual
Date of last data collection
Anticipated
30/06/2017
Actual
Sample size
Target
24
Accrual to date
Final
Recruitment outside Australia
Country [1] 8385 0
New Zealand
State/province [1] 8385 0
Otago

Funding & Sponsors
Funding source category [1] 294936 0
University
Name [1] 294936 0
University of Otago
Country [1] 294936 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
PO Box 56
Dunedin, 9054
Country
New Zealand
Secondary sponsor category [1] 293769 0
None
Name [1] 293769 0
Address [1] 293769 0
Country [1] 293769 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296310 0
Southern Health and Disability Committee
Ethics committee address [1] 296310 0
Ministry of Health
PO Box 5013
Wellington 6011
Ethics committee country [1] 296310 0
New Zealand
Date submitted for ethics approval [1] 296310 0
Approval date [1] 296310 0
26/08/2016
Ethics approval number [1] 296310 0
16/STH/111/

Summary
Brief summary
In 2000 the NMDA antagonist ketamine was reported to be an effective fast acting antidepressant in patients with major depressive disorder (MDD), and this has subsequently been confirmed in multiple studies. In addition, single doses of ketamine, at the same dose levels, were shown to have strong effects on anxiety symptoms in patients with post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD). We have recently identified similar effects in patients with refractory Generalized Anxiety Disorder (GAD) and Social Phobia (SP) – (Study 15/STH/86). In all anxiety disorders, there were rapid (within 1h) improvements in anxiety severity that were sustained for 3-7 days, not dissimilar to the responses in patients with MDD. The dose response was also similar, suggesting that the pathophysiology of diverse negative emotional disorders (anxiety, depression) may share a common neurobiology.
We have also been studying aspects of ketamine’s neurobiology, in particular its effects on expression of BDNF, in rats. BDNF is a neurotrophic hormone that appears to have an important general role in the activity of all antidepressants and many anxiolytics.
Another pharmacodynamic endpoint is cognition. One of the side effects of ketamine is changes in cognition, with changes in a range of cognitive domains following lower dose ketamine administration.. These changes were only present until 2 hours post-infusion. In a more recent trial delayed recall was found to be reduced at 40 minutes but a return to baseline was not assessed..
It is possible that ketamine’s effects on cognition are associated with its concentration in blood, and a recent review suggested that levels of 20 ng/mL could affect psychomotor performance.
There are several objectives in this randomised double blind parallel group study:
1. To evaluate the early and later effects of single doses of ketamine on BDNF concentrations in healthy volunteers, and to explore the relationship of BDNF changes with ketamine and metabolite concentrations. This research may help inform biomarker research in patient populations.
2. To evaluate the early and late effects of ketamine on EEG changes
3. To evaluate the magnitude and duration of cognitive changes following a dose of ketamine or placebo in healthy volunteers. Blood testing will also show any associations of cognitive changes with levels of ketamine and its metabolites in the participant’s bloodstream. This research may help to improve the administration method for ketamine in a clinical setting.
Trial website
none
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 70390 0
Prof Paul Glue
Address 70390 0
Department of Psychological Medicine
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 70390 0
New Zealand
Phone 70390 0
+64 21 243 3372
Fax 70390 0
Email 70390 0
[email protected]
Contact person for public queries
Name 70391 0
Dr Shona Neehoff
Address 70391 0
Department of Psychological Medicine
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 70391 0
New Zealand
Phone 70391 0
+64 3 470 9451
Fax 70391 0
Email 70391 0
[email protected]
Contact person for scientific queries
Name 70392 0
Prof Paul Glue
Address 70392 0
Department of Psychological Medicine
Dunedin School of Medicine
University of Otago
PO Box 56
Dunedin 9054
Country 70392 0
New Zealand
Phone 70392 0
+64 21 243 3372
Fax 70392 0
Email 70392 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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