Primary objective1. To investigate whether TM38837 attenuates the central effects of THCSecondary objectives2. To explore the effect of TM38837 on THC induced effects on heart rate3. To investigate the effect of 60 mg rimonabant on THC-induced CNS…
ID
Source
Brief title
Condition
- Appetite and general nutritional disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary study endpoint:
To investigate effect of TM38337 on the central effect of THC using the
following parameters:
• Body Sway
• VAS Bond and Lader (alertness, contentedness, calmness)
• VAS Bowdle (*internal*/*external* perception, *feeling high*)
Secondary outcome
Secondary study endpoints:
To investigate the effect of rimonabant on the central and heart rate effects
(including BDI-II) of THC
To explore the effect of TM38837 on THC induced effect on heart rate
The following pharmacokinetic parameters and dose-normalised pharmacokinetic
parameters will be used for the characterisation of TM38837 as well as for THC:
• Cmax
• Tmax
• T*
• AUC0**
• Subject incidence of AEs and SAEs
• Number and percentage of subjects with clinically significant changes in
vital signs (systolic blood pressure, diastolic blood pressure and pulse rate)
• Number and percentage of subjects with clinically significant changes in ECG
time intervals (PR, QRS, QT and QTc intervals)
• Number and percentage of subjects with clinically significant changes in
laboratory safety tests (haematology, clinical chemistry and urinalysis)
Background summary
Cannabinoid type 1 (CB1) receptors can be found in the central nervous system
(CNS), as well as in peripheral organs, such as the heart, liver, and adipose
tissue. CB1-agonist Δ9-tetrahydrocannabinol (THC) has been shown to increase
appetite in humans. CB1-receptor antagonists have been shown to decrease
appetite and weight in clinical studies. Moreover, CB1-antagonists have been
shown to cause beneficial metabolic changes as demonstrated in clinical studies
involving patients suffering from metabolic disorders. However, these
antagonists caused severe psychiatric side effects. Most likely, these CNS side
effects are caused by antagonists binding to and having their effect on
CB1-receptors in the brain.
Pre-clinical studies showed beneficial metabolic effects from CB1-antagonists
that only work peripherally. Because CB1-antagonists do not show acute effects
by themselves, in this study the CB-system of healthy male volunteers will be
activated by intrapulmonary administration of CB1-agonist Δ9-THC. We will
investigate a peripheral working CB1-antagonist on inhibitory effects of
central as well as peripheral THC-induced effects, and its pharmacokinetics
(PK).
Study objective
Primary objective
1. To investigate whether TM38837 attenuates the central effects of THC
Secondary objectives
2. To explore the effect of TM38837 on THC induced effects on heart rate
3. To investigate the effect of 60 mg rimonabant on THC-induced CNS and heart
rate effects
4. To perform TM38837 PK/PD-analysis, if feasible, to predict the TM38837
concentration that antagonizes THC-induced effects, and to compare the
antagonizing potential and the corresponding dose/concentration of TM38837 to
60 mg rimonabant
Study design
Double-blind, double dummy, partially randomized, triple placebo controlled,
balanced cross-over, partial parallel study of the effect of single oral
administration of TM38837 and single oral rimonabant on inhaled THC-induced
effects in 24 healthy male volunteers.
TM38837 or placeboTM38837 will be administered as two single oral doses of
100mg or 500mg. Rimonabant or placeborimonabant will be administered as one
single oral dose of 60mg.
THC or placeboTHC will be administered intrapulmonary as five single doses (4
mg) (three on day 1, two on day 2) with 2.5 hour intervals.
All subjects will receive treatment arm 1, 2, 3 and 4. Half of the subjects
will receive treatment arm 5a and the other half treatment arm 5b.
All subjects will be dosed with both TM38837 or placeboTM38837, and rimonabant
or placeborimonabant, and 5 doses of THC or placeboTHC at every treatment visit.
1 PlaceboTM38837 + Placeborimonabant + 5x PlaceboTHC
2 PlaceboTM38837 + Placeborimonabant + 5x 4 mg THC
3 100mg TM38837 + Placeborimonabant + 5x 4 mg THC
4 500mg TM38837 + Placeborimonabant + 5x 4 mg THC
5a PlaceboTM38837 + 60mg Rimonabant + 5x 4 mg THC
5b PlaceboTM38837 + Placeborimonabant + 5x 4 mg THC
Sequence of treatment arms 1-4 will be completely randomized in a balanced way.
Treatment 5 (a or b) will always be the last treatment visit.
Study burden and risks
Expected side effects of THC are: elevated heart rate, feeling high, altered
perception of time, lack of concentration, sleepiness, nausea and disturbance
of balance.
TM38837 has been tested in humans before. Side effects that were found were
diarrhea and a general feeling of unwell in few subjects and of short duration.
No serious adverse events have been reported.
Based on results of previous studies, we do not expect to find side effects
caused by rimonabant in this study. In studies with several subsequent dosing
days, the following side effects were seen: nausea, infections of the upper
airways, stomachache, vomiting, depression, dizziness, diarrhea, itch,
transpiration, muscle spasms, fatigue, hot flushes, and attitude changes with
depressive symptoms, depressive disorders, anxiety, irritability and
nervousness.
The load and the risks involved in participation in this trial are moderate.
Fremtidsvej 3
DK-2970 Horsholm
Denemarken
Fremtidsvej 3
DK-2970 Horsholm
Denemarken
Listed location countries
Age
Inclusion criteria
1. Subject is able to speak, read and understand the local language of the investigational site, is familiar with the procedures of the study, and agrees to participate in the study program by giving oral and written informed consent prior to screening evaluations.
2. Legally competent non-african/afro-american/afro-caribebean healthy male with a BMI between 18-28.5 kg/m2, inclusive
3. Age between 18-55 years, inclusive on the day the informed consent is signed.
4. Mild cannabis user for at least one year: cannabis use of no more than once a week, and able to refrain from using cannabinoids from at least 2 weeks prior to the first treatment period to the end of the last study day.
Exclusion criteria
1. History of sensitivity/idiosyncrasy to THC, TM38837 or rimonabant, compounds chemically related to these compounds, or excipients which may be employed in the study or to any other relevant drug used in the past.
2. Any clinically significant cardiovascular (e.g. hypertension), hepatic, renal, respiratory, gastrointestinal, endocrine (e.g. diabetes, dyslipidemia), immunologic, dermatologic (e.g. ancient surgically treated squamous cell carcinomas if considered significant), hematologic (including bleeding disorders), neurologic or psychiatric disease.
3. First degree relative with significant psychiatric disorder
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 | EUCTR2009-017773-38-NL |
| CCMO | NL30909.058.09 |