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

Completed

• Conditions: Alheimer's disease; 10057167

• Registration Number: NL-OMON42052
• Lead Sponsor: Centre for Human Drug Research

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 23 April 2024

Recruitment & Eligibility

• Status: Completed
• Sex: Not specified
• Target Recruitment: 28

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.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Pharmacodynamic endpoints:<br /><br>NeuroCart tests:<br /><br>• Adaptive tracking<br /><br>• Pharmaco-EEG<br /><br>• Pupil size<br /><br>• Finger tapping<br /><br>• Simple reaction time task<br /><br>• Milner Maze test<br /><br>• VAS Bond & Lader (mood, alertness and calmness)<br /><br>• N-back test<br /><br>• Visual verbal learning test; immediate recall, delayed recall, recognition<br /><br>(30 words)<br /><br><br /><br>Pharmacokinetic endpoints:<br /><br>The concentration of mecamylamine in plasma will be used to construct a PK<br /><br>model. If deemed appropriate a PK-PD model of mecamylamine will be developed.</p><br>

Secondary Outcome Measures

Name	Time	Method
<p>Safety will be assessed through reporting of adverse events, physical<br /><br>examinations, concomitant medication use, vital<br /><br>signs, clinical laboratory evaluation, hematology and blood chemistry,<br /><br>serology, drugs of abuse screening, routine<br /><br>urinalysis, alcohol breath test, electrocardiograms.</p><br>