Primary Objectives • To demonstrate if the impairment of cognitive function caused by mecamylamine administration can be diminished by an nAChR agonist or CEI.• To evaluate to what extent a single dose of 30 mg mecamylamine may cause a more…
ID
Source
Brief title
Condition
- Mental impairment disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Pharmacodynamic endpoints:
NeuroCart tests:
• Adaptive tracking
• Pharmaco-EEG
• Pupil size
• Finger tapping
• Simple reaction time task
• Milner Maze test
• VAS Bond & Lader (mood, alertness and calmness)
• N-back test
• Visual verbal learning test; immediate recall, delayed recall, recognition
(30 words)
Pharmacokinetic endpoints:
The concentration of mecamylamine in plasma will be used to construct a PK
model. If deemed appropriate a PK-PD model of mecamylamine will be developed.
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 cholinergic enhancing drugs.
The most commonly used anti-cholinergic challenge is scopolamine, a muscarinic
acetylcholine (ACh) receptor antagonist. However, using a muscarinic antagonist
to prove nicotinic agonist pharmacology would seem pharmacologically
inadequate. Furthermore, scopolamine exhibits a sedative effect following
administration which could interfere with measurements of cognitive function.
Due to increased activity in the development of selective nicotinic agonists it
would seem appealing to establish an anti-cholinergic challenge model selective
for the nicotinic receptor. Currently no model exists that allows the
pharmacology of a nicotinic agonist to be determined based on a nicotinic
antagonist. The aim of the present study is to validate a mecamylamine based
anti-nicotinergic challenge model to prove pharmacology of nicotinic agonists.
Mecamylamine is a nicotinic acetylcholine receptor antagonist, active in
peripheral autonomic ganglia, but also binding to nicotinic ACh receptors
(nAChR) present in the brain. The cholinergic system in the brain is known to
play an important role in several cognitive processes such as attention,
reaction time, and memory. A previous study confirmed that the administration
of 10 and 20 mg mecamylamine in healthy volunteers leads to a temporary,
reversible perturbation of these cognitive processes. This effect was however
small when compared to a scopolamine challenge which was also examined in this
study. In order to accurately characterize nicotinic agonist pharmacology it
was decided that a higher effect was required. In the present study a dose of
30 mg mecamylamine will be used. This is predicted to cause an increased effect
allowing for a more accurate pharmokinetic/pharmacodynamic (PK/PD) model to be
established, and allow improved characterization of the PD effects of nicotinic
agonists. Furthermore by combining the data acquired from the previous study,
it will allow a dose-effect relationship to be established (10 mg, 20 mg, 30
mg).
To validate the mecamylamine model as an effective anti-cholinergic challenge
two nicotinic receptor agonists will be used. The first, galantamine, is a
nicotinic acetylcholine receptor modulator and CEI and is used to treat
patients with AD. The second, nicotine, is a full nAChR agonist, which acts on
various nicotinic receptors which are believed to play a role in cognitive
function.
Study objective
Primary Objectives
• To demonstrate if the impairment of cognitive function caused by mecamylamine
administration can be diminished by an nAChR agonist or CEI.
• To evaluate to what extent a single dose of 30 mg mecamylamine may cause a
more pronounced cognitive impairment than the lower dose levels of 10 and 20 mg
that were previously tested.
Secondary Objectives
• To improve characterization of the mecamylamine-induced cognitive impairment
(time course and additional parameters).
• To investigate the pharmacokinetics of mecamylamine following a 30 mg dose.
• To investigate the time course of the pharmacodynamic effect of mecamylamine
and to explore the pharmacokinetic/pharmacodynamic relationship of mecamylamine
on cognition, now including the data obtained at a 30 mg dose.
• To investigate the safety and tolerability of mecamylamine 30 mg compared
with placebo.
• To investigate the safety and tolerability of a pharmacological challenge
study with mecamylamine in conjunction with nicotinic receptor agonists.
Study design
A randomized, double-blind, double-dummy, placebo-controlled, single dose,
4-way cross-over study of the reversibility of cognitive deficits induced by a
nicotinic anti-cholinergic challenge with mecamylamine by a cholinesterase
inhibitor and a nicotinic receptor agonist
Intervention
Acethylcholine receptor antagonist
• Mecamylamine hydrochloride (HCl) 30 mg (hard gelatin capsules containing 12.2
mg mecamylamine HCl (equivalent to 10 mg mecamylamine free base) and
microcrystalline cellulose as filling agent). Thirty mg are 3 capsules, oral
dose
Nicotinic receptor agonist
•Nicotine-containing patch of 21 mg nicotine, patch.
Cholinesterase inhibitor
Galantamine hydrobromide, 4 capsules of 4 gr galantamine HBR, oral.
Placebo
Matching placebos (oral and transdermal)
Study burden and risks
Blood sampling: possible pain and bruising(transient)
Study drugs:
mecamylamine: This drug was a registered antihypertensive for over 50 years and
was removed from the market for economical reasons. 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 had not been reported in these studies, but in
the postmarket surveillance as anti-hypertensive drug following AE were
described: dry mouth, constipation, vomiting, urinary retention, and mydriasis.
All are mild in severity and transient. The most commonly reported adverse
events following dosing with mecamylamine 20 mg were somnolence (64%), fatigue
(36%), nausea (36%) and dizziness (29%), and were all mild in intensity.
Galantamine and nicotine are registered drug and widely used in smoking
cessation therapy (nicotine0 and improvement of cognitive function (galantamine
HBR). The adverse event most commonly reported of galantamine was nausea.
The general toxicity of nicotine is well known. Application site reactions are
the most frequent adverse reaction associated with patches. Excessive use of
nicotine patches by those who have not been in the habit of inhaling tobacco
smoke could possibly lead to nausea, faintness or headaches.
Zernikedreef 8
Leiden 2333 CL
NL
Zernikedreef 8
Leiden 2333 CL
NL
Listed location countries
Age
Inclusion criteria
1.Healthy male subjects, 18 to 45 years of age, inclusive. Healthy status is defined by the absence of evidence of any active or chronic disease following a detailed medical and surgical history, a complete physical examination including vital signs, 12-lead ECG, haematology, blood chemistry, and urinalysis;;2.Body Mass Index (BMI) between 18 kg/m2 and 32 kg/m2;;3.Incidental smokers (defined as smoking tobacco at least once a month and no more than 5 cigarettes per day);;4.Able to participate and willing to provide written informed consent and to comply with the study 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.Any disease associated with cognitive impairment, including schizophrenia and dementia;;3.Clinically relevant abnormal laboratory results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis), electrocardiogram (ECG) and vital signs, or physical findings at screening (as judged by the investigator);;4.Presence of orthostatic hypotension as defined by a decrease of blood pressure >= 20 mmHg systolic or >= 10 mmHg diastolic, measured 2 min after standing up; ;5.Evidence of elevated blood pressure at screening of >140 mmHg systolic or >90 mmHg diastolic;;6.Positive Hepatitis B surface antigen (HBsAG), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening;;7.History of alcoholism or substance abuse within three years prior to screening;;8.Subject is unable to refrain from alcohol consumption during study confinement and at least 24 hours before screening, before dosing, and before each scheduled visit;;9.Subject is a habitual and heavy consumer of caffeinated beverages (more than 8 cups of coffee or equivalent/day) and/or is not able to refrain from use of (methyl) xanthines (e.g. coffee, tea, cola, chocolate) from 24 hours prior to dosing until discharge from the CRU for each study period;;10.Positive urine drug screen (UDS) or alcohol 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 study, from 7 days prior to dosing on Day 1 Period 1 until end of study;;12.Subject has a history of severe allergies, or has had an anaphylactic reaction to prescription or non-prescription drugs or food;;13.Known hypersensitivity to the investigational drug or comparative drug or drugs of the same class, or any of their excipients. ;14.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;;15.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; ;16.History of allergic reaction to nicotine-containing products ;17.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;;18.Donation or loss of more than 500 mL blood within three months prior to screening;;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 | EUCTR2014-001358-41-NL |
| CCMO | NL49296.058.14 |