Evoked Responses as Pharmacodynamic Biomarkers in Healthy and Schizophrenic Participants (MK-4334-007)

Study Overview
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Brief Summary
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The primary purpose of this randomized, double-blind, placebo-controlled cross-over study is to record and measure 40 Hz-auditory steady-state response (ASSR) in healthy controls (HC) and participants with mild-to-moderate schizophrenia (SZ) to determine if the mean inter-trial coherence (ITC) magnitude derived from the 40 Hz-ASSR is lower in SZ than in HC at baseline.

Detailed Description
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This is a 2-part study. Part 1 is a 2-period study in which participants receive 21 mg nicotine patches or placebo patches, each with placebo capsules, in Period 1 and Period 2 under a cross-over design. In Part 2 (Period 3), participants are randomized to receive either MK-4334 250 mg capsule or placebo capsule, each with placebo patches.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Cross-over Evaluation of Evoked Responses as Pharmacodynamic Biomarkers in Healthy Adults and Schizophrenic Patients

Conditions
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Cognitive Impairment Associated With Schizophrenia

Intervention / Treatment
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* Drug: Nicotine patch
* Drug: MK-4334
* Drug: Placebo patch
* Drug: Placebo capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HC Participants: Is in generally good health Has no history of clinically relevant neuropsychiatric illness Is a mild-to-moderate tobacco user of ≥1-year duration, smoking the equivalent of  10-15 cigarettes/day Participants with Mild-to-Moderate SZ: Has a current diagnosis of SZ with a duration ≥1 year Is clinically stable and in the residual (non-acute) phase of illness for ≥12 weeks prior to the study Is stably maintained on a regimen of up to 2 first- or second-generation antipsychotics with no dose changes >50% in combination with concomitant medication commonly prescribed to this population for ≥8 weeks prior to screening and during the study Is a mild-to-moderate tobacco user of ≥1-year duration, smoking the equivalent of  10-15 cigarettes/day All Participants: For males, agrees to be abstinent from heterosexual intercourse, or use an approved contraception method, during the study and for 90 days after the last dose of study drug For females, is not of childbearing potential Is willing to comply with restrictions on the use of nicotine or nicotine-containing products during the study Exclusion Criteria: HC Participants: Has known biological family history of psychotic disorder in a first or second degree relative Participants with Mild-to-Moderate SZ: May be excluded from participation by the investigator based on treatment history and/or performance on various screening tests All Participants: Is positive for hepatitis B surface antigen, hepatitis C antibodies, or human immunodeficiency virus (HIV) Is at imminent risk of self-harm Has had major surgery or donated blood within 4 weeks prior to screening Has evidence of cognitive impairment or significant mental disability Has a history of clinically significant abnormality or disease Has a history of cancer (malignancy) Is unable to refrain, or anticipates use, of any non-prescription drugs or herbal remedies Has participated in another clinical study within 6 weeks or 5 half-lives (whichever is greater) prior to screening

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panel A: Healthy Control Participants<br>In Part 1, HC participants receive nicotine patch + capsule placebo, and patch placebo + capsule placebo, under a cross-over design in Periods 1 and 2. In Part 2 (Period 3), HC participants are randomly assigned to receive either MK-4334 250 mg capsule + patch placebo or capsule placebo + patch placebo. | Drug: Nicotine patch<br>* Nicotine 21 mg transdermal nicotine patch.<br>Drug: MK-4334<br>* MK-4334 250 mg capsule taken by mouth.<br>Drug: Placebo patch<br>* Placebo patch.<br>Drug: Placebo capsule<br>* Placebo capsule taken by mouth.<br>|
| Experimental: Panel B: Participants with Mild-to-Moderate SZ<br>In Part 1, participants with mild-to-moderate SZ receive nicotine patch + capsule placebo, and patch placebo + capsule placebo, under a cross-over design in Periods 1 and 2. In Part 2 (Period 3), SZ participants are randomly assigned to receive either MK-4334 250 mg capsule + patch placebo or capsule placebo + patch placebo. | Drug: Nicotine patch<br>* Nicotine 21 mg transdermal nicotine patch.<br>Drug: MK-4334<br>* MK-4334 250 mg capsule taken by mouth.<br>Drug: Placebo patch<br>* Placebo patch.<br>Drug: Placebo capsule<br>* Placebo capsule taken by mouth.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean inter-trial coherence (ITC) magnitude of 40 Hz-derived auditory steady-state response (ASSR) in HC and SZ participants | The magnitude of ITC of 40 Hz-derived ASSR will be measured and recorded at baseline (Day -1) to determine if ITC differs between HC and SZ participants. | Day -1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration deviant mismatch negativity (DD-MMN) in HC and SZ participants | The mean MMN magnitude derived from baseline DD-MMN will be compared in HC and SZ participants. | Day 1 | 
| Effect of nicotine on mean ITC magnitude of 40 Hz-derived ASSR in HC and SZ participants | The effects of nicotine and placebo patches on 40 Hz-derived ASSR will be determined in HC and SZ participants on Day 1 or Day 8 in a counterbalanced order. | Day 1 or Day 8 | 
| Plasma nicotine level during event related potential (ERP) recording | Plasma nicotine levels will be determined during nicotine patch test sessions occurring on Day 1 or Day 8 in a counterbalanced order. | Day 1 or Day 8 |