Primary objectives:1. To investigate the safety and tolerability of JNJ-69095897 versus placebo after administration in healthy participants.2. To characterize the PK of JNJ-69095897 in blood, plasma, cerebrospinal fluid (CSF) and urine after…
ID
Source
Brief title
Condition
- Mood disorders and disturbances NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1. Vital signs (heart/pulse rate, systolic blood Pressure, diastolic blood
pressure, tympanic body temperature), respiratory rate, clinical labs
(chemistry, hematology, urinalysis, coagulation [Part 3 only]), adverse events
(AE), electrocardiogram (ECG) and Holter recordings.
2. Blood, plasma, CSF, and urine concentrations of JNJ-69095897 and possible
metabolites
Secondary outcome
1. Plasma 2-AG levels.
2. Plasma, blood and urine concentrations of JNJ-69095897 and possible
metabolites.
3. Plasma and CSF 2-AG levels.
Background summary
The endocannabinoid system is a biological system located both centrally and
peripherally and is involved in many physiological processes such as mood,
feeding behaviour, pain sensation, reward, stress and anxiety, glucose
metabolism, memory, and sleep.
The endocannabinoids anandamide (AEA) and 2-arachidonylglycerol (2-AG) are
retrograde messengers that modulate the presynaptic release of
neurotransmitters via cannabinoid-1 receptor (CB1R) and cannabinoid-2 receptor
(CB2R) agonism in diverse neurocircuits. Monoacylglycerol lipase (MGLL) is the
enzyme responsible for the catabolism of 2-AG into glycerol and arachidonic
acid (AA). JNJ-69095897 is a novel, orally available, brain-penetrant, potent,
reversible and selective MGLL inhibitor.
Study objective
Primary objectives:
1. To investigate the safety and tolerability of JNJ-69095897 versus placebo
after administration in healthy participants.
2. To characterize the PK of JNJ-69095897 in blood, plasma, cerebrospinal fluid
(CSF) and urine after administration in healthy participants.
Secondary objectives:
1. To investigate the effect of JNJ-69095897 versus placebo on peripheral
metabolite levels.
2. To assess the relative pharmacokinetics of JNJ-69095897 in healthy
participants, following a single oral dose in fasted condition or after a high
calorie/ high fat breakfast.
3. To assess the relationship between endogenous metabolite levels in plasma
and CSF samples from healthy participants.
Exploratory objectives:
1. To investigate the relationship between PK profile and related endogenous
metabolite levels in plasma.
2. To characterize the pharmacodynamic (PD) effect of JNJ-69095897 on CNS
function.
3. To obtain exploratory biomarker data from healthy participants.
4. Future evaluation of the PK/PD relationship of JNJ-69095897 plasma
concentrations and QT interval corrected for heart rate (QTc) following
administration in healthy participants.
Study design
The study will be conducted in three parts in healthy male participants (Part 3
also includes WONCBP): Part 1 SAD, Part 2 Food Effect, and Part 3 CSF sampling.
Part 1 will evaluate single-ascending doses of JNJ-69095897 following an
overnight fast or after a high fat breakfast using a double-blind, randomized,
placebo-controlled, dose-escalating design.
Part 2 will be an open-label study to assess the effect of food intake on
JNJ-69095897 pharmacokinetics. JNJ-69095897 will be administered after an
overnight fast or after a high fat breakfast. The dose of JNJ-69095897 to be
administered in Part 2, will be determined on the basis of the acceptability of
the safety, tolerability and PK of preceding dose levels in Part 1, and will be
not be more than the highest dose tested and was considered well tolerated in
Part 1.
Part 3 will be a randomized, double blind, single dose study, using serial CSF
sampling to investigate the effect of JNJ-69095897 on 2-AG levels in liquor.
The dose of JNJ-69095897 to be administered in part 3, will be determined once
a dose in Part 1 has been found to be acceptable based on the safety,
tolerability and pharmacokinetics of preceding dose levels in Part 1.
Intervention
JNJ-69095897 or placebo, subsequent dose levels are to be determined following
satisfactory review of the safety, tolerability, pharmacodynamic and
pharmacokinetic data from previous cohorts.
Study burden and risks
The principal mitigations for these potential risks include the maintenance of
an appropriate safety margin based on nonclinical study drug exposure,
appropriate selection of the trial population, prespecified safety monitoring
procedures, and the selection of the trial facility, where close monitoring can
be performed and rapid institution of appropriate care can be given. The
potential risks can be monitored clinically and/or with laboratory tests and
have been considered when determining the stopping rules for this clinical
trial.
A potential risk of (pre)syncope was seen in cohort 1-3 of Part 1. To mitigate
this risk, several safety measures were implemented in the study and the
exclusion criteria were adjusted to exclude participants who are at a higher
risk of (pre)syncope.
In addition to the potential risks associated with study drug administration,
there is minimal risk associated with trial procedures including scheduled,
periodic venipuncture (limited to < 500 mL) and non-invasive procedures
including vital sign assessments, electrocardiograms (ECGs), Holter an
telemetry and PD assessments. Subjects are exposed to risks associated with the
insertion, indwelling an removal of a spinal catheter in Part 3. To lower these
risks, a population of older subjects was chosen, the catheter will be inserted
by a trained physician and close monitoring will be performed in the trial
facility. Overall, the benefit-risk profile is considered appropriate for this
trial.
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Listed location countries
Age
Inclusion criteria
Part 1 and 2: Males with a minimum age of 18 years and maximum age 55 years
inclusive,
Part 3: males or female (women of non childbearing potential) with a minimum
age of 35 years and a maximum age of 75 years inclusive,
-Healthy based on physical examination, medical history, vital signs, and
12-lead ECG (means of triplicate ECG, incl. QT corrected according to
Fridericia's formula (QTcF) <= 450 msec for males and <= 470 msec for females)
performed at screening and admission to the clinical unit. Minor abnormalities
in ECG, blood pressure and heart rate, which are not considered to be of
clinical significance by the investigator, are acceptable, with the exception
of bradycardia <= 45 bpm on 12-lead safety ECG, that will be exclusionary at
screening, admission to the clinical unit or prior to the first dose on the
dosing day.
-Healthy based on clinical laboratory tests performed at screening. If the
results of the serum chemistry panel including liver enzymes, hematology, or
urinalysis are outside the normal reference ranges, the participant may be
included at the discretion of the investigator, provided the investigator
judges the abnormalities to be not clinically
significant. This determination must be recorded in the participant's source
documents and initialed by the investigator.
-Participant has a body mass index (BMI) between 18.0 and 30.0 kg/m2 inclusive
(BMI=weight/height2).
Please see protocol for remaining inclusion criteria.
Exclusion criteria
1. Has a history of or current significant medical illness including (but not
limited to) cardiac arrhythmias or other cardiac disease, orthostatic
hypotension, liver or renal insufficiency, significant cardiac, vascular,
pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic,
psychiatric, or metabolic disturbances. or any other illness that the
investigator considers should exclude the participant.
2. Has a diagnosis or suspicions of any sleep disorder in the last 6 months or
current complaints of sleep disturbance, irregular sleep schedule or shift
work; habitual daytime naps; travel across time zones in the last 4 weeks or
daytime symptoms attributable to unsatisfactory sleep.
3. Has a history of or current major or clinically relevant psychiatric
disorder as classified according to Diagnostic and Statistical Manual of Mental
Disorders (5th edition) (DSM-5) (e.g., mood, anxiety disorders, psychotic
disorder etc.).
4. Has a current or recent (within the past year) history of clinically
significant suicidal ideation (corresponding to a score of >= 3 for ideation) or
any suicidal behavior within the past year, as validated on the C-SSRS at
screening or baseline. Participants with a prior suicide attempt of any sort,
or history of prior serious suicidal ideation/plan should be carefully screened
for current suicidal ideation and only included at the discretion of the
investigator.
5. Has known allergies, hypersensitivity, or intolerance to study intervention
or its excipients.
6. Has a decrease in systolic blood pressure of 20 mm Hg or a decrease in
diastolic blood pressure of 10 mm Hg within three minutes of standing compared
with blood pressure from the supine position, during orthostatic blood pressure
measurements at screening or baseline.
7. Has 3-second or more pauses in 12-lead ECG Holter based on 24 hours Holter
monitoring conducted at screening
8. Has a personal or family history of recurrent (exertional) syncope or
presyncope.
9. Has previously experienced vasovagal syncope's.
Design
Recruitment
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 | EUCTR2021-000609-26-NL |
| CCMO | NL77617.056.21 |
| Other | t.b.d. |