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

Phase 1

Completed

Conditions: Cognitive Impairment Associated With Schizophrenia

Interventions: Drug: Nicotine patch
Drug: MK-4334
Drug: Placebo patch
Drug: Placebo capsule

Registration Number: NCT05136690

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: The primary purpose of this randomized, double-blind, placebo-controlled cross-over study was 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: This is a 2-part study. Part 1 was a 2-period study in which participants received either 21 mg nicotine patches and then placebo patches or vice versa, with each patch co-administered with placebo capsules, in a counterbalanced order. In Part 2, participants were randomized to receive either MK-4334 250 mg capsule or placebo capsule, each with placebo patches.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 38

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Panel A: Healthy Control Participants	Placebo patch	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.
Panel B: Participants with Mild-to-Moderate SZ	Placebo patch	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.
Panel A: Healthy Control Participants	Nicotine patch	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.
Panel A: Healthy Control Participants	Placebo capsule	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.
Panel B: Participants with Mild-to-Moderate SZ	Nicotine patch	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.
Panel B: Participants with Mild-to-Moderate SZ	MK-4334	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.
Panel B: Participants with Mild-to-Moderate SZ	Placebo capsule	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.
Panel A: Healthy Control Participants	MK-4334	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.

Primary Outcome Measures

Name	Time	Method
Mean Inter-trial Coherence (ITC) Magnitude of 40 Hz-derived Auditory Steady-state Response (ASSR) in HC and SZ Participants at Baseline	Day -1 (Baseline)	The ITC magnitude derived from the 40Hz ASSR is presented. ASSR is measured following a short stream of click trains with a 500 msec inter-train interval (duration), at standard tone and at 40Hz tone. The magnitude of ITC represents the phase consistency of oscillatory activities, in response to EEG coherence at 40Hz stimulation. ITC as a unit of measure is expressed as frequency (40Hz) vs time (msec).

Secondary Outcome Measures

Name	Time	Method
Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-A, N100-A, and P3A-A Tests	Day -1 (Baseline)	The mean MMN magnitude derived from baseline DD-MMN will be compared in HC and SZ participants. MMN is measured by subtracting the averaged response to a set of standard stimuli form the average response to deviant stimuli, and taking the amplitude of this difference in a given timepoint. Tests include amplitude of MMN (MMN-A), amplitude of negative peak at 100 msec (N100-A), and amplitude of P3A (P3A-A).
Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-L, N100-L, and P3A-L Tests	Day -1 (Baseline)	The mean MMN magnitude derived from baseline DD-MMN will be compared in HC and SZ participants. The mean MMN magnitude derived from baseline DD-MMN will be compared in HC and SZ participants. MMN is measured by subtracting the averaged response to a set of standard stimuli form the average response to deviant stimuli, and taking the amplitude of this difference in a given timepoint. Tests include latency of MMN (MMN-A), latency of negative peak at 100 msec (N100-A), and latency of P3A (P3A-A).
Effect of Nicotine on Mean ITC Magnitude of 40 Hz-derived ASSR in HC and SZ Participants Compared to Baseline	Day -1 (baseline), Day 1, and Day 8	The effects of nicotine and placebo on in the change from baseline in 40-Hz-derived ASSR were determined in HC and SZ participants on Day 1 or Day 8 in a counterbalanced order, and compared to baseline ASSR. ASSR is measured following a short stream of click trains with a 500 msec inter-train interval (duration), at standard tone and at 40Hz tone. The magnitude of ITC represents the phase consistency of oscillatory activities, in response to EEG coherence at 40Hz stimulation. ITC as a unit of measure is expressed as frequency (40Hz) vs time (msec).
Plasma Nicotine Concentration 2 Hours After Patch Application (C2h) Assessed During Event Related Potential (ERP) Recording Sessions	2 hours after patch application on Day 1 or Day 8	Plasma nicotine levels were determined 2 hours after patch application (C2h) during 21 mg nicotine patch test sessions. Participants received either a nicotine or placebo patch on Days 1 and 8 in a counterbalanced order.

Trial Locations

Locations (2): Collaborative Neuroscience Research, LLC ( Site 0002)
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Long Beach, California, United States
Hassman Research Institute Marlton Site ( Site 0001)
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Marlton, New Jersey, United States