Cognitive Impairment Associated With Schizophrenia
Conditions
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.
Interventions
DRUGNicotine patch
Nicotine 21 mg transdermal nicotine patch.
DRUGMK-4334
MK-4334 250 mg capsule taken by mouth.
DRUGPlacebo patch
Placebo patch.
DRUGPlacebo capsule
Placebo capsule taken by mouth.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants with schizophrenia (SZ) and healthy control (HC) participants were enrolled at 2 study sites in the US.
Participants by arm
| Arm | Count |
|---|---|
| Panel A: Healthy Control Participants In Period 1, HC participants received both nicotine patches and placebo patches in a counterbalanced order. All patches were co-administered with placebo capsules. In Period 2, participants received MK-4334 250 mg capsule and placebo capsule in counterbalanced order. All capsules were co-administered with placebo patches. | 13 |
| Mild-to-Moderate SZ Participants In Period 1, SZ participants received both nicotine patches and placebo patches in a counterbalanced order. All patches were co-administered with placebo capsules. In Period 2, participants received MK-4334 250 mg capsule and placebo capsule in counterbalanced order. All capsules were co-administered with placebo patches. | 25 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Withdrawal by Subject | 0 | 1 |
| Period 2 | Lost to Follow-up | 0 | 3 |
| Period 2 | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Mild-to-Moderate SZ Participants | Total | Panel A: Healthy Control Participants |
|---|---|---|---|
| Age, Continuous | 45.0 years STANDARD_DEVIATION 7.8 | 42.9 years STANDARD_DEVIATION 8.4 | 38.9 years STANDARD_DEVIATION 8.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 36 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants | 32 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 1 Participants |
| Sex: Female, Male Male | 22 Participants | 34 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 37 | 0 / 27 | 0 / 38 |
| other Total, other adverse events | 8 / 37 | 0 / 27 | 4 / 38 |
| serious Total, serious adverse events | 0 / 37 | 0 / 27 | 0 / 38 |
Outcome results
Primary
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).
Time frame: Day -1 (Baseline)
Population: All participants who complied with the protocol sufficiently to ensure the the data are likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Panel A: Healthy Control Participants | Mean Inter-trial Coherence (ITC) Magnitude of 40 Hz-derived Auditory Steady-state Response (ASSR) in HC and SZ Participants at Baseline | 0.432 ITC (40Hz*msec) | Standard Deviation 0.15 |
| Mild-to-Moderate SZ Participants | Mean Inter-trial Coherence (ITC) Magnitude of 40 Hz-derived Auditory Steady-state Response (ASSR) in HC and SZ Participants at Baseline | 0.364 ITC (40Hz*msec) | Standard Deviation 0.16 |
Secondary
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).
Time frame: Day -1 (Baseline)
Population: All participants who complied with the protocol sufficiently to ensure the the data are likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Panel A: Healthy Control Participants | Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-A, N100-A, and P3A-A Tests | MMN-A Test | -5.207 µV | Standard Deviation 2.558 |
| Panel A: Healthy Control Participants | Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-A, N100-A, and P3A-A Tests | N100-A Test | -1.616 µV | Standard Deviation 1.966 |
| Panel A: Healthy Control Participants | Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-A, N100-A, and P3A-A Tests | P3A-A Test | 2.974 µV | Standard Deviation 0.774 |
| Mild-to-Moderate SZ Participants | Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-A, N100-A, and P3A-A Tests | MMN-A Test | -3.932 µV | Standard Deviation 2.031 |
| Mild-to-Moderate SZ Participants | Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-A, N100-A, and P3A-A Tests | N100-A Test | -1.117 µV | Standard Deviation 1.332 |
| Mild-to-Moderate SZ Participants | Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-A, N100-A, and P3A-A Tests | P3A-A Test | 3.121 µV | Standard Deviation 1.263 |
Secondary
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).
Time frame: Day -1 (Baseline)
Population: All participants who complied with the protocol sufficiently to ensure the the data are likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Panel A: Healthy Control Participants | Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-L, N100-L, and P3A-L Tests | MMN-A Test | 172.615 msec | Standard Deviation 27.122 |
| Panel A: Healthy Control Participants | Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-L, N100-L, and P3A-L Tests | N100-A Test | 90.462 msec | Standard Deviation 17.704 |
| Panel A: Healthy Control Participants | Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-L, N100-L, and P3A-L Tests | P3A-A Test | 284.308 msec | Standard Deviation 38.104 |
| Mild-to-Moderate SZ Participants | Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-L, N100-L, and P3A-L Tests | MMN-A Test | 178.880 msec | Standard Deviation 25.469 |
| Mild-to-Moderate SZ Participants | Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-L, N100-L, and P3A-L Tests | N100-A Test | 87.680 msec | Standard Deviation 14.739 |
| Mild-to-Moderate SZ Participants | Duration Deviant Mismatch Negativity (DD-MMN) in HC and SZ Participants: MMN-L, N100-L, and P3A-L Tests | P3A-A Test | 280.480 msec | Standard Deviation 26.691 |
Secondary
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).
Time frame: Day -1 (baseline), Day 1, and Day 8
Population: All participants who complied with the protocol sufficiently to ensure the the data are likely to exhibit the effects of treatment, according to the underlying scientific model.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Panel A: Healthy Control Participants | Effect of Nicotine on Mean ITC Magnitude of 40 Hz-derived ASSR in HC and SZ Participants Compared to Baseline | ITC1500 Nicotine | 0.054 ITC (40Hz*msec) | Standard Deviation 0.109 |
| Panel A: Healthy Control Participants | Effect of Nicotine on Mean ITC Magnitude of 40 Hz-derived ASSR in HC and SZ Participants Compared to Baseline | ITC1500 Placebo | 0.000 ITC (40Hz*msec) | Standard Deviation 0.103 |
| Mild-to-Moderate SZ Participants | Effect of Nicotine on Mean ITC Magnitude of 40 Hz-derived ASSR in HC and SZ Participants Compared to Baseline | ITC1500 Nicotine | 0.040 ITC (40Hz*msec) | Standard Deviation 0.043 |
| Mild-to-Moderate SZ Participants | Effect of Nicotine on Mean ITC Magnitude of 40 Hz-derived ASSR in HC and SZ Participants Compared to Baseline | ITC1500 Placebo | 0.010 ITC (40Hz*msec) | Standard Deviation 0.093 |
Secondary
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.
Time frame: 2 hours after patch application on Day 1 or Day 8
Population: All participants who complied with the protocol sufficiently to ensure the the data are likely to exhibit the effects of treatment, according to the underlying scientific model. Participants received nicotine on either Day 1 or Day 8; results are shown according to actual day of nicotine patch application.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Panel A: Healthy Control Participants | Plasma Nicotine Concentration 2 Hours After Patch Application (C2h) Assessed During Event Related Potential (ERP) Recording Sessions | Nicotine on Day 1 | 160.5 nM | Geometric Coefficient of Variation 24 |
| Panel A: Healthy Control Participants | Plasma Nicotine Concentration 2 Hours After Patch Application (C2h) Assessed During Event Related Potential (ERP) Recording Sessions | Nicotine on Day 8 | 119.6 nM | Geometric Coefficient of Variation 52 |
| Mild-to-Moderate SZ Participants | Plasma Nicotine Concentration 2 Hours After Patch Application (C2h) Assessed During Event Related Potential (ERP) Recording Sessions | Nicotine on Day 1 | 163.3 nM | Geometric Coefficient of Variation 26 |
| Mild-to-Moderate SZ Participants | Plasma Nicotine Concentration 2 Hours After Patch Application (C2h) Assessed During Event Related Potential (ERP) Recording Sessions | Nicotine on Day 8 | 159.3 nM | Geometric Coefficient of Variation 24 |