Primary Objectives* To investigate the effects of PO and IV S-ketamine and its metabolite S-norketamine on functional CNS tests up to 6h (acute effects) and 24h (delayed effects) after administration using NeuroCart test battery in healthy subjects…
ID
Source
Brief title
Condition
- Mood disorders and disturbances NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Tolerability / safety endpoints
- treatment-emergent adverse events (AEs) and serious adverse events (SAEs)
- adverse events leading to premature discontinuation of study drug
- epileptic seizures as a result of TMS
- laboratory safety, vital signs and ECG
Pharmacokinetic endpoints
Pharmacokinetic variables (including but not limited to Cmax, AUC0-*, clearance
(CL), Vss, terminal half-life (t*)) for the different compounds and metabolites
will be evaluated if deemed appropriate. For analysis concentrations of
S-ketamine, S-norketamine, and S-hydroxynorketamine will be obtained in plasma,
according to the schedule specified in table 1. Data may be used for PK or
PK-PD modelling.
Pharmacodynamic endpoints
NeuroCart
* Saccadic eye movements
* Smooth pursuit eye movements
* Body sway
* Adaptive tracking
* Visual Analog Scales (VAS) Bond and Lader
* Visual Analog Scale (VAS) Bowdle
* Digit Symbol Substitution Test (DSST)
TMS-EMG
* rMT measured with single pulse TMS
* Peak-to-peak amplitude of the motor evoked potential (MEP) measured with
single pulse TMS (stimulation intensity: 120% rMT)
* Short intracortical inhibition (SICI) measured with paired pulse TMS at an
interstimulus
* interval (ISI) of 2 ms (stimulation intensity: conditioning pulse 80% rMT,
test pulse: 120% rMT)
* Long intracortical inhibition (LICI) measured with paired pulse TMS at ISIs
50, 100 and 300 ms (stimulation intensity: conditioning and test pulse 120%
rMT).
TMS-EEG
* Amplitude of the TMS evoked potential (TEP) measured with single pulse TMS
and paired pulse TMS at ISIs 2, 50, 100 and 300 ms
EEG
* Resting state EEG
* P300/ active auditory oddball
* 40Hz Auditory Steady State Response (ASSR)
* Auditory Sensory Gating (ASG)
Secondary outcome
Oxford ETB
* Facial Expression Recognition Task (FERT) - perception of social cues
* Emotional Categorisation Task (ECAT) - attention to affective information
* Faces Dot Probe Task (FDOT) - attention to affective information
* Emotional Recall Task (EREC) - memory for affective information
* Emotional Recognition Memory Task (EMEM) - memory for affective information
MEQ30
* scores on *mystical* (subdomain)
* scores on *positive mood* (subdomain)
* scores on *space/time* (subdomain)
* scores on *ineffability* (subdomain)
Background summary
Treatment resistant major depressive disorder (TR-MDD) is a serious and
potentially lethal psychiatric illness with a lifetime prevalence of up to 2%.1
The non-competitive glutamate N-Methyl-D-aspartate receptor (NMDAR) antagonist
ketamine demonstrates rapid antidepressant efficacy 24h after administration in
TR-MDD patients.2 It therefore is a unique compound in terms of onset of
antidepressant effects compared to the conventional monoaminergic
antidepressant drugs, and as a consequence, is currently being investigated as
a potential treatment for TR-MDD in clinical practice.
Study objective
Primary Objectives
* To investigate the effects of PO and IV S-ketamine and its metabolite
S-norketamine on functional CNS tests up to 6h (acute effects) and 24h (delayed
effects) after administration using NeuroCart test battery in healthy subjects
* To investigate the effects of PO and IV S-ketamine and its metabolite
S-norketamine on cortical excitability up to 6h (acute effects) and 24h
(delayed effects) after administration using TMS-EEG and TMS-electromyography
(EMG) in healthy subjects
Secondary Objectives
* To explore effects of PO and IV S-ketamine and its metabolite S-norketamine
on emotional processing using ETB at 24h after administration (delayed effects)
in healthy volunteers
* To explore effects of PO and IV S-ketamine and its metabolite S-norketamine
on brain activity up to 6h (acute effects) and 24h (delayed effects) after
administration using EEG in healthy subjects
* To further characterize the pharmacokinetics and pharmacodynamics of IV vs
oral S-ketamine and its metabolite S-norketamine
* To characterize the subjective dissociative effects of S-ketamine and its
metabolite S-norketamine retrospectively using the Mystical Experiences
Questionnaire (MEQ30)
Exploratory Objective
* To assess the relationship between personality characteristics and individual
response to S-ketamine using the Dutch Personality Questionnaire
(DPQ)/Nederlandse Persoonlijkheidsvragenlijst(NPV), Cloninger Temperament and
Character Inventory (TCI) and Spielberger State-Trait Anxiety Inventory*Trait
inventory (STAI-DY).
Study design
Randomized, double-blind, double-dummy, placebo-controlled, 4-way crossover
study in 16 healthy subjects. The study consists of a medical screening (from 6
weeks prior to visit 1) and training period (from 3 weeks prior to visit 1) to
ensure subjects meet eligibility criteria, followed by 4 in-clinic periods (of
aproximately 2 days) separated with a wash-out period of 14 to 21 days, during
which subjects will return for a short visit in which PD measurements will be
done on Day 7 post-dose. A final follow-up visit takes place at least 14 days
after last dose
Intervention
S-ketamine 0.2 mg/kg oral solution in single dose
S-ketamine 0.45 mg/kg oral solution in single dose
S-ketamine 0.4 mg/kg IV over 40 min
placebo: intravenous saline, oral matching solution (double-dummy)
Study burden and risks
Intranasal S-ketamine has been FDA-approved for the treatment of TR-MDD and
intravenous S-ketamine has been approved for anaesthesia and/or pain treatment
in several EU countries, including the Netherlands. However, S-ketamine will be
administered in lower (antidepressant/subanaesthetic) dosages in the current
study. S-ketamine has acute psychomimetic effects at the planned dose levels in
this study which have been well-characterized previously.7 In higher dosages it
is an anaesthetic drug with a favourable safety profile.91 Psychomimetic
symptoms as described above, will wane off over time and disappear by 4 to 6h
post-dose. Nonetheless, subjects will remain in the clinic for 30h post
administration under supervision and will be discharged by a physician only if
their medical condition allows. The subjects can be closely monitored for any
adverse signs during the different treatments. In addition, subjects will not
be allowed drive a car and should not engage in activities that require
operating vehicles or dangerous machinery following administration of
S-ketamine. Therefore, providing the protocol is adhered to, careful
observation and medical management will minimize any associated risk in this
study.
Preclinical data may be of less importance as extensive clinical experience
exists for racemic ketamine as well as S-ketamine. However, clinical use is
often short-term. Therefore, long-term effects in humans have mostly been
observed through reports of recreational abuse. In the current study, only
single doses will be administered on each occasion.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
1. Healthy female or male subjects, 18 to 45 years of age, inclusive. Healthy
status is defined by absence of evidence of any active or chronic disease
following a detailed medical, surgical and psychiatric history, a complete
physical examination including vital signs, 12-lead electrocardiogram (ECG),
haematology, blood chemistry, and urinalysis.
2. Able to participate and willing to give written informed consent and to
comply with the study restrictions.
3. Use of any form of birth control is required for heterosexual subjects of
childbearing potential who are sexually active during the study, either used by
the subject or their sexual partner.
4. Able to read and understand English at a sufficient level in order to
participate in the ETB.
Exclusion criteria
1. Positive test for drugs of abuse at screening or pre-dose.
2. The subject has a positive pregnancy test.
3. History (within 3 months of screening) of alcohol consumption exceeding 2
standard drinks per day on average.
4. History or symptoms of any significant disease including (but not limited
to), neurological, endocrine, cardiovascular, respiratory, gastrointestinal,
hepatic, or renal disorder.
5. The subject has a previous or current, or a family history of, a clinically
significant psychiatric disorder, including substance use disorder.
6. A history or family history of epilepsy, seizures or convulsions.
7. Having metal objects in brain or skull.
8. The subject has a history of intracranial mass lesion, hydrocephalus and/or
head injury or trauma.
8. Having a cochlear implant or implanted deep brain stimulator.
9. Abnormal sleeping pattern (e.g. working night shifts).
10. Resting motor threshold (rMT) of more than 75% of the maximum stimulator
output, measured using TMS-EMG during screening.
11. Systolic blood pressure (SBP) greater than 140 mmHg during screening. The
measurement may be repeated before randomization to confirm eligibility or
judged to be clinically irrelevant for healthy subjects.
12. Use of any medications within 14 days of study drug administration, or less
than 5 half-lives (whichever is longer).
13. Use of more than 5 cigarettes (or other tobacco or nicotine products with
equivalent nicotine dose) daily within the previous month before the first dose
administration, and/or unable or unwilling to not smoke during the in-house
periods.
15. Regular recreational use of illicit drugs (notably ketamine) within 12
months of screening.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-002083-31-NL |
| CCMO | NL73916.056.20 |
| OMON | NL-OMON28424 |