Functional Magnetic Resonance Imaging (fMRI) Investigation of Nicotine Withdrawal Symptoms

Study Overview
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Brief Summary
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A single center, double blind, randomized, placebo controlled, two-treatments, two-period crossover study conducted in adult smokers.

Detailed Description
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The main objective of this study is to use blood oxygen level-dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) in abstinent smokers to directly evaluate the effect of the 4 milligrams (mg) nicotine lozenge on brain activation associated with visual attention. The experimental task featured 3 conditions: 1. a highly demanding cognitive/attention task, 2. a simple cognitive/attention task, and 3. simply look at a '+' symbol. During the experiment these conditions are each presented a number of times in an alternating manner while acquiring images.

Official Title
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Simultaneous fMRI/EEG of the 4 mg Nicotine Lozenge in Relief of Cognitive Impairment Associated With Nicotine Withdrawal

Conditions
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Smoking

Intervention / Treatment
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* Drug: Nicotine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Weight and size Body mass index (BMI) within the range 19.0-32.0 kg/m. Able to fit comfortably within the MR scanner. Smoking Status Cigarette smokers that consume their first manufactured cigarette (i.e., not self rolled cigarettes) within 30 min of waking. Individuals who have smoked regularly for at least a year. Females of childbearing potential who are, in the opinion of the investigator, practicing a reliable method of contraception. Understands and is willing, able and likely to comply with all study procedures and restrictions. Good general health with (in the opinion of the examining study doctor) no clinically significant and relevant abnormalities of medical history, physical examination or clinical laboratory test. Demonstrates understanding of the study and willingness to participate as evidenced by voluntary written informed consent and has received a signed and dated copy of the informed consent form. Exclusion Criteria: Women who are pregnant or who have a positive urine pregnancy test or who are breast-feeding. Disease/Illness Any clinically significant medical history or abnormality found on physical examination, laboratory assessment or electrocardiogram (ECG) at screening which, in the opinion of the investigator, could interfere with the interpretation of efficacy or safety data or which otherwise would contraindicate participation in a clinical trial. Current or recent history or presence of a neurological diagnosis (not limited to but including for example, stroke, traumatic brain injury, carotid arterial sclerotic disease, epilepsy, space occupying lesions, multiple sclerosis, Parkinson's disease, vascular dementia, transient ischemic attack, schizophrenia, major depression etc.) that may influence the outcome or analysis of the scan results. Contraindications to MR scanning Intracranial aneurysm clips History of intra-orbital metal fragments that have not been removed by a doctor (as confirmed by orbital X-Ray). Inner ear implants. Tattoos with metal containing inks or piercings that can not be removed except those, which, in the opinion of the Investigator, will not interfere with the study procedures or compromise safety. History of claustrophobia or subject feels unable to lie still on their back for a period of 90 min in the MR scanner. Presence of a cardiac pacemaker or other electronic device or ferromagnetic metal foreign bodies in vulnerable positions as assessed by a standard pre-MRI questionnaire supported by plain X-Rays where appropriate. Prior/Concomitant Medication Use of any central nervous system (CNS) active, prescription medication within 14 days of first treatment visit. Use of any over the counter (OTC) medication within 14 days of each treatment visit except those, which, in the opinion of the Investigator, will not interfere with the study procedures or compromise safety. Paracetamol (up to 2 g) may be taken up to 24 hrs prior to each treatment visit. Current use of any nicotine replacement therapy. Clinical Study/Experimental Medication Participation in another clinical study or receipt of an investigational drug within 3 months of the first treatment visit. Previous participation in this study. Known or suspected intolerance or hypersensitivity to the study materials (or closely related compounds) or any of their stated ingredients. Substance abuse History of regular alcohol consumption exceeding an average weekly intake of more than 14 units per week for females, 21 units per week for males, or an average daily intake greater than 2 units for females and 3 units for males. Past history of drug abuse, excluding nicotine, or has tested positive for urine drugs of abuse at the screening or either treatment visit. Consumption of any alcoholic beverages within 24 hours of the treatment visits (as indicated by either a positive breath alcohol test or in the opinion of the Investigator). Consumption of large quantities of xanthine containing beverages (e.g., coffee, tea, cola, chocolate etc, more than an average of five cups or glasses per day).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nicotine lozenge<br>Nicotine lozenge containing 4 mg of nicotine to be placed in mouth and suck to dissolution. | Drug: Nicotine<br>* Nicotine lozenge containing 4 mg of nicotine<br>|
| Placebo Comparator: Placebo lozenge<br>Placebo lozenge to be placed in mouth and suck to dissolution. | Drug: Placebo<br>* Placebo lozenge<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Mean Change in Blood Oxygen-level Dependent (BOLD) Scores During Rapid Visual Information Processing (RVIP) Task | In RVIP task, participant responded to consecutive sequences of three odd or three even numbers by pressing the corresponding response button as quickly and accurately as possible. During a control task, participant responded to single occurrences of the number 0. BOLD fMRI signals evaluated different brain regions of interest (ROI) during RVIP task. Brain ROIs identified were right and left anterior insula, anterior putamen, parietal cortex, premotor cortex, visual cortex, dorsal anterior cingulate cortex, substantia nigra and thalamus. | Approximately 2 hours post dose administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Response Time for Correct Responses During RVIP Task | During the RVIP task, participants responded to consecutive sequences of three odd or three even numbers by pressing the corresponding response button as quickly and accurately as possible. During a control task, participants responded to single occurrences of the number 0. Mean response time for correct responses was determined. | Approximately 2 hours post dose administration | 
| Mean Percentage of Correct Responses During RVIP Task | Percentage of correct responses during RVIP task was determined | Approximately 2 hours post dose administration | 
| Percent Mean Change in BOLD Scores During Divided Attention (DIA) Task | BOLD fMRI signals evaluated different brain ROIs during DIA task which comprised of three conditions: i) Sustained visual attention wherein participant responded to letter s every time it appeared in a continuous stream of letters on a screen; ii) Sustained auditory attention wherein participant responded to the number 8 each time in appeared in a continuous stream of numbers presented through headphones; iii) Divided attention task auditory and visual stimuli wherein participant responded to occurrences of s (visual) and 8 (auditory) simultaneously. Brain ROIs were right and left parietal cortex, visual cortex, superior occipital cortex and right premotor cortex. | Approximately 2 hours post dose admininstration | 
| Mean Response Time for Correct Responses During DIA Task | DIA task comprised of three conditions: i) Sustained visual attention wherein participant responded to letter s every time it appeared in a continuous stream of letters on a screen; ii) Sustained auditory attention wherein participant responded to the number 8 each time in appeared in a continuous stream of numbers presented through headphones; iii) Divided attention task auditory and visual stimuli wherein participant responded to occurrences of s (visual) and 8 (auditory) simultaneously. Mean response time for correct responses was determined. | Approximately 2 hours post dose administration | 
| Mean Percentage of Correct Responses During DIA Task | Mean percentage of correct responses during DIA task was determined. | Approximately 2 hours post dose administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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nicotine, therapy, fMRI/EEG, replacement