The specific goals of the study are:- To identify which dose(s) of mecamylamine cause cognitive and memory impairment as demonstrated using the NeuroCart CNS test battery- To investigate the safety and tolerability of mecamylamine by comparison with…
ID
Source
Brief title
Condition
- Neurological disorders NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Main Parameters:
Pharmacokinetics: Levels of mecamylamine and scopolamine will be determined in
blood samples collected at the time points depicted in the Time and Events
schedule. The following parameters will be calculated: cmax, tmax, t1/2el.
Additional exploratory analyses of PK parameters may be performed as necessary.
Also, a PK/PD-model will be created. To this end, the PK samples will be taken
within a 20 minute window to match PD measurements.
Pharmacodynamics: The following PD criteria will be evaluated (see the Time and
Events Schedule for the exact time of PD measurements):
• Adaptive tracking
• Neuro-endocrine parameters (LH, prolactin, cortisol)
• Pharmaco-EEG
• Pupil size
• Saccadic eye movements
• Smooth pursuit eye movement
• Body sway
• Finger tapping
• Simple reaction time task
• Stroop test
• VAS Bond & Lader (mood, alertness and calmness)
• Visual n-back test
• Visual verbal learning test (30 words).
Secondary outcome
Safety will be assessed through reporting of adverse events, physical
examinations, concomitant medication use, vital signs, clinical laboratory
evaluation, hematology and blood chemistry, serology, drugs of abuse screening,
routine urinalysis, alcohol breath test, electrocardiograms.
Background summary
Anti-cholinergic pharmacological challenges have been used previously to induce
cognitive disturbances reminiscent of Alzheimer*s Disease (AD), but their use
is more appropriate for proof of pharmacology of pro-cholinergic drugs. The
most well known anti-cholinergic challenge method is with scopolamine, a
muscarinic acetylcholine (ACh) receptor antagonist, and has been used amongst
others to prove pharmacology of cholinesterase inhibitors (CEI). Currently, few
new CEI*s are being developed, but there is more activity in the development of
selective nicotinic receptor agonists. Using a muscarinic antagonist to prove
pharmacology of a nicotinic agonist would seem pharmacologically inadequate
(even though some reversal of scopolamine induced cognitive deficits has been
shown to occur due to nicotinic agonists). The aim of the present study is to
set up an anti-nicotinergic challenge method in order to better prove
pharmacology of nicotinic agonists. Mecamylamine is a nicotinic ACh receptor
antagonist, active in peripheral autonomic ganglia, but also binding to
nicotinic ACh receptors present in the brain. The cholinergic system in the
brain is hypothesized to play an important role in several cognitive processes
such as attention, reaction time, and memory. Administration of mecamylamine to
healthy volunteers has been shown to lead to a temporary, reversible
perturbation of these cognitive processes. An anti-nicotinic pharmacological
challenge using mecamylamine has been described previously, but with the
current study we aim to gain more and time-dependent information on
pharmacodynamic (PD) effects of mecamylamine. Simultaneously, pharmacokinetic
(PK) characterization will be performed in order to confirm and extent
non-compartmental PK data. Moreover, the PK/PD relationships of mecamylamine
have not been addressed yet. Assessing simultaneously PD effects of scopolamine
and mecamylamine using the Neurocart test battery, a computerized system for
psychological and cognitive measurements including cognitive test performance,
will allow comparison of anti-cholinergic challenges without the limitations of
post hoc analysis.
Study objective
The specific goals of the study are:
- To identify which dose(s) of mecamylamine cause cognitive and memory
impairment as demonstrated using the NeuroCart CNS test battery
- To investigate the safety and tolerability of mecamylamine by comparison with
placebo.
- To determine the pharmacokinetic (PK) profile of mecamylamine after oral
administration.
- To investigate the time course of the pharmacodynamic (PD) effects of
mecamylamine as well as the PK/PD relationships in healthy volunteers
- Compare the effects of mecamylamine, a nicotinergic ACh receptor antagonist,
on cognitive function and memory with the effects of scopolamine, a muscarinic
ACh receptor antagonist
Study design
Single center, double-blind, double-dummy, placebo-controlled, randomized
4-period way crossover study with mecamylamine (nicotinergic antagonist) and
scopolamine (muscarinergic antagonist) in healthy volunteers.
Intervention
Drugs and Dosages:
Active Compound: Mecamylamine hydrochloride
Dosage form: Hard gelatin caspsules containing 12.2 mg mecamylamine HCl
(equivalent to 10 mg mecamylamine free base) and microcrystalline cellulose
as filling agent
Strength: 10 mg (1 capsule + placebo), 20 mg (2 capsules)
Placebo: Gelatin capsule containing microcrystalline cellulose
Active Compound: Scopolamine Hydrobromide
Dosage form: Solution for intravenous (i.v.) administration
Strength: 0.1 mg/mL
Placebo: saline
Scopolamine hydrobromide (5 mL) will be administered as a 15-minute i.v.
infusion (i.e. 0.33 mL/min). The total dose will be 0.5 mg scopolamine
hydrobromide that is equivalent to 0.35 mg scopolamine as free base.
Study burden and risks
Mecamylamine:
Mecamylamine has been more than 50 year on the market in the US. A side effect
likely to occur is orthostatic hypotension. When using as pharmacological
challenge, mild and transient adverse have been reported: sedation (7%),
*feeling fuzzy*. Other anticholinergic adverse effects have not been reported
in these studies.
Scopolamine:
Scopolamine is well known to block postganglionic autonomic sites, producing an
array of anticholinergic symptoms. Less known CNS symptoms, such as
hallucinations, are mentioned only sparingly or anecdotally. Because of its
shorter half-life, and far better defined PK properties and the experience of
CHDR in scopolamine challenges using this dosage and form of dosage, the chance
of risks is considered minimal. Following adverse effects have been reported in
a previous CHDR study: anticholinergic symptoms (97%), nausea (8%), dizziness
(7%) and palpitations (6%). In general, the scopolamine treatment was well
tolerated by all other subjects. All symptoms were mild and transient.
Zernikedreef 10
2333 CL Leiden
NL
Zernikedreef 10
2333 CL Leiden
NL
Listed location countries
Age
Inclusion criteria
1. Signed informed consent document
2. Healthy, male volunteers aged between 18 and 45 years
3. Body Mass Index between 18 kg/m2 and 32 kg/m2
4. Non-smokers for at least 1 year
5. Willingness to comply with study procedures and restrictions
Exclusion criteria
1. Clinically relevant history of abnormal physical or mental health interfering with the study as determined by medical history taking and physical examinations obtained during the screening visit as judged by the investigator;
2. Clinically relevant abnormal laboratory results, electrocardiogram (ECG) and vital signs, or physical findings at screening (as judged by the investigator);
3. Presence of orthostatic hypotension as defined by a decrease of blood pressure >=10 mmHg systolic or >= 20 mmHg diastolic measured 2 min after standing up
4. Positive test for hepatitis B, C or HIV;
5. History of alcoholism or substance abuse within three years prior to screening;
6. Subjects unable to refrain from alcohol use from 24hours prior to dosing on Day 1 Periods 1-5 until discharge from the CRU for each study period;
7. Used tobacco and/or nicotine-containing products within one year of dosing on Day 1 Period 1;
8. Evidence of elevated blood pressure at screening of >140 mmHg systolic or >90 mmHg diastolic;
9. Subject is a habitual and heavy consumer of caffeinated beverages (more than 6 cups of coffee or equivalent/day) at screening and/or is not able to refrain from use of (methyl) xanthines (e.g. coffee, tea, cola, chocolate) from 12 hours prior to dosing until discharge from the CRU for each study period;
10. Positive urine drug screen (UDS) or alcohol or cotinine test at screening and/or Day 1 of each period;
11. Subject is unable to refrain from the use of concomitant medication which, in the opinion of the investigator, interferes with their ability to participate in the trial, from 7 days prior to dosing on Day 1 Period 1 until the follow-up study visit;
12. Subject has a history of severe allergies, or has had an anaphylactic reaction to prescription or non-prescription drugs or food;
13. History or clinical evidence of any disease and/or existence of any surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drugs (mecamylamine or scopolamine);
14. Currently using any nicotine replacement therapy, smoking cessation medications or remedies, including varenicline (Chantix ®) or have used any nicotinic products for smoking cessation within 3 months of screening; history of allergic reaction to nicotine-containing products
15. Participation in an investigational drug trial in the 3 months prior to administration of the initial dose of study drug (Day 1 Period 1) or more than 4 times per year;
16. Donation of blood/plasma outside limits of Sanquin Blood Supply Foundation guidelines of approximately 500 mL or significant blood loss;
17. Have a history of an allergic reaction to nicotine containing products;
18. Subject does not have veins suitable for canula placement on both arms;
19. Any other condition that in the opinion of the investigator would complicate or compromise the study, or the well being of the subject.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-001392-36-NL |
| CCMO | NL40218.058.12 |