Primary ObjectiveTo evaluate the effect of a single 84-mg dose of intranasal esketamine compared to placebo, on next day driving performance and repeated administration of 84 mg intranasal esketamine on same-day driving performance as assessed by…
ID
Source
Brief title
Condition
- Mood disorders and disturbances NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
On-the-road driving test
In each study period, a validated car driving test will be performed at a
predetermined time after dosing. The subject*s task will be to operate a
specially instrumented vehicle over a 100-km primary highway circuit, while
maintaining a constant speed (95 km/h) and steady lateral position between the
delineated boundaries of the right (slower) traffic lane. SDLP (cm), ie, the
weaving of the car, is the primary outcome variable. Standard deviation of
speed (SDS, km/h) will be a secondary variable. Mean lateral position (MLP, +/-
cm), and mean speed (MS, km/h) are control variables
Secondary outcome
Karolinska Sleepiness Scale
(KSS), a subject-reported assessment used to rate sleepiness on a scale of 1 to
9, ranging from *extremely alert* (1) to *very sleepy, great effort to keep
awake, fighting sleep (9).
Subjective assessments of driving performance
the perceived quality of their driving performance on a visual analog scale
from 0 (*I drove exceptionally poorly*) to 20 (*I drove exceptionally
well*) around a midpoint of *I drove normally*.
A pharmacogenomic blood sample (10 mL) will be collected on Day 1 from all
subjects for analysis of cytochrome P450 CYP2B6.
Safety and tolerability will be assessed from the time of consent until the end
of the study. Safety and tolerability assessments will include: adverse events,
12-lead electrocardiograms (ECGs), vital signs, clinical laboratory results,
and physical examinations. The C-SSRS will be performed to assess suicidal
ideation and behavior, and the CADSS will be administered to assess
treatment-emergent dissociative symptoms.
Background summary
Ketamine and esketamine (S-ketamine, the S enantiomer of ketamine) are approved
medications and widely used for the induction and maintenance of anesthesia via
intramuscular or intravenous administration. The desired analgesic-anesthetic
effects of ketamine and esketamine are attributed to the
blockade of ionotropic N-methyl-D-aspartate (NMDA) glutamate receptors. The
antidepressive mechanism of action of ketamine and esketamine is distinct from
conventional monoaminergic treatments. Ketamine profoundly affects fast
excitatory glutamate transmission, increases brain-derived
neurotrophic factor release, and stimulates synaptogenesis.
Due to the higher NMDA receptor affinity of esketamine over arketamine
(R-ketamine), Janssen Research & Development is developing esketamine for
antidepressant therapy, which can be administered via a non-invasive and
rapidly absorbed route (intranassaly).
Study objective
Primary Objective
To evaluate the effect of a single 84-mg dose of intranasal esketamine compared
to placebo, on next day driving performance and repeated administration of 84
mg intranasal esketamine on same-day driving performance as assessed by the
mean difference of standard deviation of lateral position (SDLP) from an
on-road driving test.
Secondary Objectives
To evaluate the effect of esketamine on:
- Subjective driving ability and mental effort scale
- Karolinska Sleepiness Scale
- Efficacy measured by the Montgomery Asberg Depression Rating Scale (MADRS)
- Safety and tolerability with special attention to:
a. Effects on suicidal ideation/behavior measured by the Columbia Suicide
Severity Rating Scale (C-SSRS)
b. Effects on dissociative symptoms using the Clinician-Administered
Dissociative States Scale (CADSS)
To evaluate the potential relationship between changes in driving performance
and the plasma concentration of esketamine and noresketamine.
Study design
This is a placebo- and ethanol-controlled, single-center study in men and women
with MDD consisting of 2 parts.
The total duration of the study is up to 98 days. This includes a screening
period of 21 days, a Part A consisting of three 2-day periods with 5 to 14 days
of washout between each study drug administration, the next day, a drive test
is performed after the administration of ethanol, the positive control, or
placebo. Part B consists of 25 days, with 5 to 14 days of washout between the
last dose in Part A and the first dose in Part B. Administration of the study
medciation takes place on day 4,8,11,15 and a skills test is performed on day
1,11,18 and 25. End-of-study procedures that will take place 7 to 10 days after
the last dose in Part B.
Intervention
In Part A, intranasal esketamine or placebo (according to the sequence to which
the subject randomized) will be administered on Day 1 of each period as
follows: each 28-mg dose of esketamine will be self-administered as 2 sprays
totaling one 100-µL of solution into each nostril at Time 0, 5, and
10 minutes for a total of 84 mg. Sprays to each nostril should occur in rapid
succession (ie, no waiting between sprays in each nostril at each time point).
Oral ethanol or placebo will begin to be administered 45 minutes before the
scheduled start of the driving test on Day 2.
In Part B, intranasal placebo (1 spray of placebo solution in each nostril at
Time 0, 5, and 10 minutes) will be administered in the morning on Day 1.
Intranasal esketamine will be administered in the morning on Days 4, 8, 11, 15,
18, 22, and 25. The driving test will start 6 hours after administration of
intranasal placebo or esketamine on the respective study days.
Study burden and risks
Patients will be exposed to a compound that can cause cognitive and psychiatric
symptoms. During the study, regular assessrnents of the safety and tolerability
will be made and evaluated. Also, patients will be resident in the research
unit for dose administration and supervised by the medical staff of the
clinical unit during the study day(s) and brought home. When a patient decides
to terminate his/her participation in the study, he/she will not be allowed to
leave the clinic within 2 hours after dosing Subjects will be advised not to
drive a car themselves or operate machines until at least 24 hours after
dosing.
The driving study will be executed using a specially equipped car. A licensed
driving instructor (having access to dual controls) guards the safety of the
subject during the test. The test vehicle and the test execution will be
covered by an insurance.
Dr. Paul Janssenweg 150
Tilburg 5000 LT
NL
Dr. Paul Janssenweg 150
Tilburg 5000 LT
NL
Listed location countries
Age
Inclusion criteria
Willing and able to adhere to the prohibitions and restrictions specified in this protocol
If a woman, must have a negative serum beta human chorionic gonadotropin pregnancy test at screening and a negative urine pregnancy test on Day 1 of Period 1 in Part A and prior to study drug administration in Part B
Comfortable with selfadministration of intranasal medication and able to follow instructions provided
Normal visual acuity (corrected or uncorrected)
Based on selfreport, able to consume an amount of alcohol that typically produces a blood alcohol concentration (BAC) of 0.05 percent (that is, 2 to 3 alcoholic drinks ingested within 2 hours on a single occasion)
Exclusion criteria
Current or prior diagnosis of psychosis/psychotic or bipolar disorder
Primary sleep disorder, such as insomnia, requiring pharmacological intervention at Screening
Clinically significant abnormal values for hematology, clinical chemistry, or urinalysis at screening or Day 1 of Period 1 as deemed appropriate by the investigator
Clinically significant abnormal physical examination, vital signs, or 12lead electrocardiogram (ECG) at screening or Day 1 of Period 1 as deemed appropriate by the investigator
History of moderate or severe use disorder according to Diagnostic and Statistical Manual of Mental Disorders (DSMIV or DSM5) criteria within 1 year before screening or positive test result(s) for alcohol and/or drugs of abuse (such as barbiturates, opiates, cocaine, cannabinoids, amphetamines, and benzodiazepines) at screening and Day 1 of Period 1
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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-002424-86-NL |
| CCMO | NL58993.056.16 |