The Effect of Nicotine on Arousal, Cognition and Social Cognition in Schizophrenic Patients

A Double-Blind, Placebo-Controlled, Randomized Three-Way Crossover Study to Investigate The Effect of Nicotine on Arousal, Standard Cognitive Tasks And Social Cognition in Patients With Schizophrenia (Smoking and Non-Smoking)

This study in patients with stable schizophrenia will investigate the effect of nicotine on arousal, cognitive task and social cognition after acute dose administration.

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Cognition Disorders
• Intervention / Treatment: Other: A643 (nicotine); Other: A643 (nicotine); Drug: placebo

Detailed Description

This is a double-blind (neither physician nor patient knows the name of the assigned drug), placebo-controlled, randomized (study drug assigned by chance), three-way-crossover trial (patients may receive different interventions sequentially during the trial) in patients with stable schizophrenia. The three-way-crossover treatment phase will consist of three blinded treatment periods separated by a wash out period (the period allowed for the entire administered drug to be eliminated from the body) of 2 to 7 days. The study duration for each patient will be approximately 8 weeks. Each patient enrolled will be randomized to receive Treatment A (1mg nicotine per dosing), Treatment B (2mg nicotine per dosing) or Treatment C (placebo) during one of their treatment period. The study drug (nicotine or placebo) will be administered three times daily on Day 1 of each treatment phase as a mouth spray, separated 2 to 3 hours from each other (i.e. 0h; and 2 to 3h; and 4 to 6h post first dosing). Three different blocks of cognitive assessments will follow, one after each drug administration. Safety evaluations include adverse event monitoring, vital signs and clinical laboratory tests. Each patient participating will receive 3 identical study drug administrations per dosing day (2 to 3 hours from each other), resulting in an overall dose of 3 mg nicotine (Treatment A), 6 mg nicotine (Treatment B) or 0 mg nicotine (Treatment C) per dosing day. By the end of the study, after the 3-way crossover, each patient will have received 9 mg nicotine via mouth spray.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Early Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• In- or outpatients with schizophrenia stably treated (same primary medication) for at least 2 months with antipsychotic therapy (treatment with more than 1 antipsychotic drug is acceptable provided dose levels have been stable for > 2 months). Fluctuations in dose levels of the primary antipsychotic treatment are acceptable provided the dose levels remain constant as from 2 weeks prior to dosing
• A known (by the site) disease history of at least 12 months
• DSM-IV criteria for Schizophrenia
• Willing to be hospitalized during the treatment periods of the study
• Body mass index (BMI) between 18 and 35 kg/m2, inclusive (BMI = weight/height2)
• Women must be: postmenopausal (for at least 12 months), surgically sterile (have had a hysterectomy or bilateral oophorectomy, tubal ligation, or otherwise be incapable of pregnancy), abstinent (at the discretion of the investigator/per local regulations), or if sexually active, be practicing a highly effective method of birth control and must agree to continue to use the same method of contraception throughout the study
• Women of childbearing potential must have a negative serum pregnancy test at screening and a negative urine pregnancy test at admission (each study period)
• Smoking on average a minimum of 15 cigarettes (or equivalent) per day within 6 months prior to study drug administration (only for Cohort 1)

Exclusion Criteria:

• Female patients who are pregnant or breastfeeding
• Clinically significant abnormal values for clinical chemistry, hematology or urinalysis at screening. It is expected that laboratory values will generally be within the normal range for the laboratory, though minor deviations, which are not considered to be of clinical significance to the investigator, are acceptable. Values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2 fold ULN will be allowed
• Clinically significant abnormal physical examination, vital signs or 12-lead ECG at screening
• A DSM-IV axis I diagnosis other than schizophrenia that has been the focus of treatment or cause of disability in the last 6 months (such as Major Depressive Episode)
• Evidence of substance dependence other than nicotine (DSM-IV) in the last 6 months
• History of or current significant medical illness including (but not limited to) cardiac arrhythmias or other cardiac disease, unmanaged high BP, hematological disease, bronchospastic respiratory disease, renal or hepatic insufficiency, Parkinson's disease, infection (HIV, Hepatitis C), or any other illness that the Investigator considers should exclude the subject (Subjects with mild hypertension, lipid abnormalities, diabetes mellitus or thyroid disease are allowed if no significant treatment changes were required in the past 6 months)
• Use of anti-parkinsonian agents in the past 2 months
• Suicidal risk (assessed by the investigator), prior attempts to suicide, command hallucinations and / or hopelessness
• Smoking cigarettes (or equivalents) or the use of nicotine based products within 3 months prior to study drug administration (only for Cohort 2)
• Current use of any medication for smoking cessation such as nicotine replacement therapy, bupropion or varenicline
• History of epilepsy or fits or unexplained black-outs

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 001; A643 (nicotine) 1mg oromucosal nicotine spray- three times daily during each treatment period	Other: A643 (nicotine); 1mg oromucosal nicotine spray- three times daily during each treatment period; Other: A643 (nicotine); 2mg oromucosal nicotine spray- three times daily during each treatment period
Experimental: 002; A643 (nicotine) 2mg oromucosal nicotine spray- three times daily during each treatment period	Other: A643 (nicotine); 1mg oromucosal nicotine spray- three times daily during each treatment period; Other: A643 (nicotine); 2mg oromucosal nicotine spray- three times daily during each treatment period
Placebo Comparator: 003; placebo placebo - three times daily during each treatment period	Drug: placebo; placebo - three times daily during each treatment period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Event related potentials (P50, P300, N100) and measures of standard cognition and social cognition	1 hour post dose

Secondary Outcome Measures

Outcome Measure	Time Frame
Nicotine exposure	predose and 5 min post each dosing

Collaborators and Investigators

• Sponsor: Janssen Pharmaceutica N.V., Belgium
• Collaborators: Agentschap voor Innovatie door Wetenschap en Technologie

Study record dates

Study Major Dates

• Study Start: May 1, 2010
• Primary Completion: December 7, 2022
• Study Completion (Actual): March 1, 2011

Study Registration Dates

• First Submitted: August 19, 2010
• First Submitted That Met QC Criteria: August 19, 2010
• First Posted (Estimate): August 23, 2010

Study Record Updates

• Last Update Posted (Estimate): March 20, 2012
• Last Update Submitted That Met QC Criteria: March 19, 2012
• Last Verified: March 1, 2012

More Information

Terms related to this study

• Keywords: Schizophrenia; Cognition; Symptomatic treatment; Cognitive deficits
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Cognition Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Ganglionic Stimulants; Nicotinic Agonists; Cholinergic Agonists; Nicotine
• Other Study ID Numbers: CR017263

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No