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

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

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.

Study Overview

• Status: Completed
• Conditions: Cognitive Impairment Associated With Schizophrenia
• Intervention / Treatment: Drug: Nicotine patch; Drug: MK-4334; Drug: Placebo patch; Drug: Placebo capsule

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.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Long Beach, California, United States, 90806
      • Collaborative Neuroscience Research, LLC ( Site 0002)
  • New Jersey
    • Marlton, New Jersey, United States, 08053
      • Hassman Research Institute Marlton Site ( Site 0001)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Panel A: Healthy Control Participants; 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; Nicotine 21 mg transdermal nicotine patch.; Drug: MK-4334; MK-4334 250 mg capsule taken by mouth.; Drug: Placebo patch; Placebo patch.; Drug: Placebo capsule; Placebo capsule taken by mouth.
Experimental: Panel B: Participants with Mild-to-Moderate SZ; 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; Nicotine 21 mg transdermal nicotine patch.; Drug: MK-4334; MK-4334 250 mg capsule taken by mouth.; Drug: Placebo patch; Placebo patch.; Drug: Placebo capsule; Placebo capsule taken by mouth.

What is the study measuring?

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 at 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).	Day -1 (Baseline)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-A, N100-A, and P3A-A Tests	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).	Day -1 (Baseline)
Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-L, N100-L, and P3A-L Tests	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).	Day -1 (Baseline)
Effect of Nicotine on Mean ITC Magnitude of 40 Hz-derived ASSR in HC and SZ Participants Compared to Baseline	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).	Day -1 (baseline), Day 1, and Day 8
Plasma Nicotine Concentration 2 Hours After Patch Application (C2h) Assessed During Event Related Potential (ERP) Recording Sessions	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.	2 hours after patch application on Day 1 or Day 8

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

Helpful Links

• Merck Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): April 27, 2022
• Primary Completion (Actual): September 23, 2022
• Study Completion (Actual): November 4, 2022

Study Registration Dates

• First Submitted: November 19, 2021
• First Submitted That Met QC Criteria: November 19, 2021
• First Posted (Actual): November 29, 2021

Study Record Updates

• Last Update Posted (Actual): November 29, 2024
• Last Update Submitted That Met QC Criteria: October 8, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Schizophrenia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Neurotransmitter Agents; Cholinergic Agents; Ganglionic Stimulants; Nicotinic Agonists; Cholinergic Agonists; Nicotine
• Other Study ID Numbers: 4334-007; MK-4334-007 (Other Identifier: Merck)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No