Schizophrenia
Conditions
Brief summary
This 3-part dose titration study will assess elpipodect safety, tolerability, pharmacokinetics (PK), and central nervous system activity. Part 1 (Panels A and B) will assess elpipodect administered as monotherapy in participants with schizophrenia. Part 2 (Panel C) will assess elpipodect administered as add-on to atypical antipsychotic treatment in participants with schizophrenia. Part 3 (Panel D) will assess monotherapy with elpipodect in healthy participants, including those of Japanese descent. The primary hypothesis is that there is at least one dose of elpipodect that is generally safe and well-tolerated which will have the desired PK parameters in participants with schizophrenia.
Detailed description
As specified by Phase 1 protocol-flexible language in the protocol, modifications to the dose or dosing regimen can be made to achieve the scientific goals of the trial objectives and/or ensure appropriate safety of the trial participants. The proposed doses for each Part may be adjusted downward based on evaluation of safety, tolerability, and pharmacokinetic data observed in previous panels.
Interventions
DRUGElpipodect
MK-8189, oral, 2 mg and/or 10 mg tablets, taken QD for a total daily dose of 2 mg, 4 mg, 8 mg, 10 mg, 12 mg, 14 mg, 16 mg, 20 mg, or 40 mg
DRUGPlacebo
Placebo matching oral 2 mg and/or 10 mg MK-8189 tablets, taken QD
DRUGBase Monotherapy
For Part 2 only: participants need to be on monotherapy with an atypical antipsychotic medication (eg, Olanzapine, Quetiapine, Paliperidone, Asenapine, Iloperidone, Aripirprazole, Lurasidone, Risperidone \[not to exceed daily dose of 6 mg\], or Ziprasidone.) The participant should be on a stable and well tolerated treatment regimen for at least 2 months prior to screening. NOTE: Clozapine is not allowed.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
INCLUSION CRITERIA FOR SCHIZOPHRENIA PARTICIPANTS * Male or non-pregnant and non-breast feeding female. If participant is male with a female partner of child-bearing potential, participant must agree to use a medically acceptable method of contraception during the trial and for 120 days after the last dose of trial drug. If their partner is pregnant, males must agree to use a condom * Body Mass Index (BMI) ≥ 18.5 and ≤ 40 kg/m\^2 * Meet diagnostic criteria for schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria with the onset of the first episode being no less than 2 years prior to study entry * Be in the non-acute phase of illness and clinically stable for 3 months prior to screening * History of receiving and tolerating antipsychotic medication within the usual dose range employed for schizophrenia * Participants with hypothyroidism, diabetes, high blood pressure, chronic respiratory conditions or other mild forms of these medical conditions could be considered as candidates for study enrollment if their condition is stable and the prescribed dose and regimen of medication is stable for at least 3 months prior to screening and there are no expected changes in comedication during the study * Has a negative urinary drug screen at screening INCLUSION CRITERIA FOR HEALTHY PARTICIPANTS * Male, or non-pregnant and non-breast feeding female of Japanese or non-Japanese descent. If participant is male with a female partner of child-bearing potential, participant must agree to use a medically acceptable method of contraception during the trial and for 120 days after the last dose of trial drug. If their partner is pregnant, males must agree to use a condom * Body Mass Index (BMI) ≥ 18.5 and ≤ 35 kg/m\^2 * In good health * Nonsmoker and/or has not used nicotine or nicotine-containing products (e.g., nicotine patch) for at least approximately 3 months * Has a negative urinary drug screen at screening
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 1, 4, 8, 11 and 14 pre-dose and 24 hours post-dose | C24hr was defined as the concentration of MK-8189 observed in plasma at the 24-hour nominal sampling time after administration of MK-8189. In participants receiving MK-8189, blood samples were collected pre-dose and 24 hours post-dose to estimate C24hr following MK-8189 administration. As specified by the protocol, C24hr was analyzed by part, dose and dosing schedule. Due to differing dosing schedules, some time points were not applicable for certain arms/doses as indicated by zero participants analyzed entered in the table. Per protocol, healthy participants (Part 3) and participants receiving placebo were excluded from C24 analysis. |
| Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 1 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 24 hours post-dose; Days 4, 8, 11 pre-dose and 6, 10, 16, 24 hours post-dose; Day 14 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 hours post-dose | AUC was defined as a measure of MK-8189 exposure that was calculated as the product of plasma drug concentration and time. The linear-up-log down rule was used to estimate AUC. Blood samples were collected pre-dose and up to 24 hours post-dose to estimate AUC(0-24hr) following MK-8189 administration. As specified by the protocol, AUC(0-24hr) was analyzed by part, dose and dosing schedule. Due to differing dosing schedules, some time points were not applicable for certain arms/doses as indicated by zero participants analyzed entered in the table. Per protocol, healthy participants (Part 3) and participants receiving placebo were excluded from AUC(0-24hr) analysis. |
| Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 1 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 24 hours post-dose; Days 4, 8, 11 pre-dose and 6, 10, 16, 24 hours post-dose; Day 14 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48 hours post-dose | Cmax was defined as the maximum concentration of MK-8189 observed in plasma. Blood samples were collected pre-dose and up to 48 hours post-dose at multiple time points to estimate Cmax following MK-8189 administration. As specified by the protocol, Cmax was analyzed by part, dose and dosing schedule. Due to differing dosing schedules, some time points were not applicable for certain arms/doses as indicated by zero participants analyzed entered in the table. Per protocol, healthy participants (Part 3) and participants receiving placebo were excluded from Cmax analysis. |
| Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 1 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 24 hours post-dose; Days 4, 8, 11 pre-dose and 6, 10, 16, 24 hours post-dose; Day 14 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48 hours post-dose | Tmax was defined as the time required post dose to reach a maximum plasma concentration of MK-8189. It was estimated as the actual sampling time at the highest MK-8189 plasma concentration. Blood samples were collected pre-dose and up to 48 hours post-dose at multiple time points to estimate Tmax following MK-8189 administration. As specified by the protocol, Tmax was analyzed by part, dose and dosing schedule. Due to differing dosing schedules, some time points were not applicable for certain arms/doses as indicated by zero participants analyzed entered in the table. Per protocol, healthy participants (Part 3) and participants receiving placebo were excluded from Tmax analysis. |
| Time Required for Plasma Concentration of MK-8189 to Decrease by Half (Apparent t1/2) in Schizophrenia Participants on Day 14 | Day 14 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48 hours post-dose | t1/2 was defined as the time required to divide the MK-8189 plasma concentration by half after reaching pseudo-equilibrium. At least three quantifiable post-Cmax, terminal phase concentrations collected were used to calculate the apparent t1/2. Blood samples were collected pre-dose and up to 48 hours post-dose at multiple time points on Day 14 to estimate t1/2 following MK-8189 administration. As specified by the protocol, t1/2 was analyzed by part, dose and dosing schedule. Due to differing dosing schedules, the Day 14 timepoint was not applicable for certain arms/doses as indicated by zero participants analyzed entered in the table. Per protocol, healthy participants (Part 3) and participants receiving placebo were excluded from t1/2 analysis. |
| Number of Participants Experiencing an Adverse Event (AE) | Up to Day 28 | An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced at least one AE were reported. |
| Number of Participants Who Discontinue From Study Treatment Due to an AE | Up to Day 14 | An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | Baseline and Day 13 | MMN is a response to deviant tone (stimuli) measured in electroencephalogram (EEG) signals. Difference in deviant EEG waveform amplitude from standard amplitude over time indicates MMN; this difference at peak waveform is MMN peak amplitude. Schizophrenic participants show reduced response to deviant stimuli. Peak amplitude change from baseline (Day -1) to Day 13 was reported. A higher change indicates improved response to deviant stimuli. Scalp EEG signals were collected using a standard system array of 19 electrodes denoted by nomenclature of scalp placement: C3, C4, Cz, F3, F4, F7, F8, Fp1, Fp2, Fz, O1, O2, P3, P4, Pz, T3, T4, T5, T6. As specified by the protocol, MK-8189 add-on therapy schizophrenia participants (Part 2), healthy participants (Part 3) and all placebo-treated participants were excluded from MMN analyses. Per protocol, MMN analyses were planned and executed in all schizophrenia participants receiving MK-8189 monotherapy, irrespective of different dosing schedules. |
| Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | Baseline and Day 13 | MMN is a response to deviant tone (stimuli) measured in EEG signals. Difference in deviant EEG waveform amplitude from standard amplitude over time indicates MMN; AUC was measured as the product of MMN amplitude and time. Schizophrenic participants show reduced response to deviant stimuli. AUC change from baseline (Day -1) to Day 13 was reported. A higher change indicates improved response to deviant stimuli. Scalp EEG signals were collected using a standard system array of 19 electrodes denoted by nomenclature of scalp placement: C3, C4, Cz, F3, F4, F7, F8, Fp1, Fp2, Fz, O1, O2, P3, P4, Pz, T3, T4, T5, T6. As specified by the protocol, MK-8189 add-on therapy schizophrenia participants (Part 2), healthy participants (Part 3), and all placebo-treated participants were excluded from MMN analyses. Per protocol, MMN analyses were planned and executed in all schizophrenia participants receiving MK-8189 monotherapy, irrespective of different dosing schedules. |
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Pre-assignment details
Forty-three schizophrenia participants and 12 healthy volunteers were randomized to either MK-8189 or placebo in Part 1 Panels A & B, Part 2 Panel C, or Part 3 Panel D. MK-8189 dose and schedule were modified for participants based on tolerability.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 Panel A & B MK-8189 Monotherapy 2-4 mg: Schizophrenic Participant with Schizophrenia received monotherapy of MK-8189 in escalating doses: 2 mg once daily (QD) Days 1-4 and 4 mg QD Days 5-14 | 1 |
| Part 1 Panel A & B MK-8189 Monotherapy 2-12 mg: Schizophrenic Participants with Schizophrenia received monotherapy of MK-8189 in escalating doses: 2 mg QD Days 1-4, 4 mg QD Days 5-8, 8 mg QD Days 9-11, and 12 mg QD Days 12-14. | 13 |
| Part 1 Panel A & B Placebo Monotherapy: Schizophrenic Participants with Schizophrenia received dose-matched placebo to MK-8189 monotherapy on Days 1-14 | 4 |
| Part 2 Panel C MK-8189 Add-on Therapy 2-12 mg: Schizophrenic Participants with Schizophrenia received add-on therapy of MK-8189 in escalating doses: 2 mg QD Days 1-4, 4 mg QD Days 5-8, 8 mg QD Days 9-11, and 12 mg QD Days 12-14 | 13 |
| Part 2 Panel C MK-8189 Add-on Therapy 4-16 mg: Schizophrenic Participants with Schizophrenia received add-on therapy of MK-8189 in escalating doses: 4 mg QD Days 1-4, 8 mg QD Days 5-8, 12 mg QD Days 9-11, and 16 mg QD Days 12-14 | 6 |
| Part 2 Panel C Placebo Add-on Therapy: Schizophrenic Participants with Schizophrenia received dose-matched placebo to MK-8189 add-on therapy on Days 1-14 | 6 |
| Part 3 Panel D MK-8189 Monotherapy 2-12 mg: Healthy Healthy participants received monotherapy of MK-8189 in escalating doses: 2 mg QD Days 1-4, 4 mg QD Days 5-8, 8 mg QD Days 9-11, and 12 mg QD Days 12-14 | 9 |
| Part 3 Panel D MK-8189 Monotherapy 2-8 mg: Healthy Healthy participant received monotherapy of MK-8189 in escalating doses: 2 mg QD Days 1-4, 4 mg QD Days 5-8, and 8 mg QD days 9-14 | 1 |
| Part 3 Panel D Placebo Monotherapy: Healthy Healthy participants received dose-matched placebo to MK-8189 monotherapy on Days 1-14 | 2 |
| Total | 55 |
Baseline characteristics
| Characteristic | Part 1 Panel A & B MK-8189 Monotherapy 2-4 mg: Schizophrenic | Part 1 Panel A & B MK-8189 Monotherapy 2-12 mg: Schizophrenic | Part 1 Panel A & B Placebo Monotherapy: Schizophrenic | Part 2 Panel C MK-8189 Add-on Therapy 2-12 mg: Schizophrenic | Part 2 Panel C MK-8189 Add-on Therapy 4-16 mg: Schizophrenic | Part 2 Panel C Placebo Add-on Therapy: Schizophrenic | Part 3 Panel D MK-8189 Monotherapy 2-12 mg: Healthy | Part 3 Panel D MK-8189 Monotherapy 2-8 mg: Healthy | Part 3 Panel D Placebo Monotherapy: Healthy | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 21.0 Years | 44.2 Years STANDARD_DEVIATION 8.7 | 44.0 Years STANDARD_DEVIATION 9 | 43.8 Years STANDARD_DEVIATION 8.9 | 41.7 Years STANDARD_DEVIATION 14.7 | 44.5 Years STANDARD_DEVIATION 7.6 | 43.3 Years STANDARD_DEVIATION 8.7 | 55.0 Years | 43.0 Years STANDARD_DEVIATION 5.7 | 43.4 Years STANDARD_DEVIATION 9.4 |
| Sex: Female, Male Female | 0 Participants | 3 Participants | 1 Participants | 6 Participants | 3 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 17 Participants |
| Sex: Female, Male Male | 1 Participants | 10 Participants | 3 Participants | 7 Participants | 3 Participants | 5 Participants | 7 Participants | 0 Participants | 2 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 12 | 0 / 10 | 0 / 10 | 0 / 4 | 0 / 18 | 0 / 13 | 0 / 17 | 0 / 17 | 0 / 17 | 0 / 6 | 0 / 6 | 0 / 25 | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 9 | 0 / 2 | 0 / 12 |
| other Total, other adverse events | 8 / 14 | 6 / 12 | 2 / 10 | 6 / 10 | 3 / 4 | 0 / 18 | 3 / 13 | 6 / 17 | 7 / 17 | 7 / 17 | 2 / 6 | 4 / 6 | 1 / 25 | 5 / 10 | 5 / 10 | 6 / 10 | 2 / 9 | 2 / 2 | 0 / 12 |
| serious Total, serious adverse events | 0 / 14 | 0 / 12 | 0 / 10 | 0 / 10 | 0 / 4 | 0 / 18 | 0 / 13 | 0 / 17 | 0 / 17 | 0 / 17 | 0 / 6 | 0 / 6 | 0 / 25 | 0 / 10 | 0 / 10 | 0 / 10 | 1 / 9 | 0 / 2 | 0 / 12 |
Outcome results
Primary
Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants
AUC was defined as a measure of MK-8189 exposure that was calculated as the product of plasma drug concentration and time. The linear-up-log down rule was used to estimate AUC. Blood samples were collected pre-dose and up to 24 hours post-dose to estimate AUC(0-24hr) following MK-8189 administration. As specified by the protocol, AUC(0-24hr) was analyzed by part, dose and dosing schedule. Due to differing dosing schedules, some time points were not applicable for certain arms/doses as indicated by zero participants analyzed entered in the table. Per protocol, healthy participants (Part 3) and participants receiving placebo were excluded from AUC(0-24hr) analysis.
Time frame: Day 1 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 24 hours post-dose; Days 4, 8, 11 pre-dose and 6, 10, 16, 24 hours post-dose; Day 14 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 20, 24 hours post-dose
Population: Schizophrenia participants who received ≥1 dose of MK-8189, complied with the protocol and had AUC(0-24hr) data available for Days 1, 4, 8, 11, or 14. Due to differing dosing schedules, some time points were not applicable for some arms (shown by 0 participants analyzed). Per protocol, healthy participants (Part 3) and placebo arms were excluded.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 4 | 2160 nM*hr | Geometric Coefficient of Variation 69.6 |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 1 | 1090 nM*hr | Geometric Coefficient of Variation 29.8 |
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 8 | 4390 nM*hr | Geometric Coefficient of Variation 54.4 |
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 14 | 4100 nM*hr | — |
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 11 | 4720 nM*hr | — |
| Part 1 Panel A & B MK-8189 Monotherapy 8 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 11 | 9770 nM*hr | Geometric Coefficient of Variation 40.8 |
| Part 1 Panel A & B MK-8189 Monotherapy 12 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 14 | 12300 nM*hr | Geometric Coefficient of Variation 27 |
| Part 2 Panel C MK-8189 Add-on Therapy 2 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 4 | 1810 nM*hr | Geometric Coefficient of Variation 42.7 |
| Part 2 Panel C MK-8189 Add-on Therapy 2 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 1 | 1040 nM*hr | Geometric Coefficient of Variation 27.3 |
| Part 2 Panel C MK-8189 Add-on Therapy 4 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 8 | 4300 nM*hr | Geometric Coefficient of Variation 31.5 |
| Part 2 Panel C MK-8189 Add-on Therapy 4 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 4 | 5740 nM*hr | Geometric Coefficient of Variation 57.8 |
| Part 2 Panel C MK-8189 Add-on Therapy 4 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 1 | 2600 nM*hr | Geometric Coefficient of Variation 41 |
| Part 2 Panel C MK-8189 Add-on Therapy 8 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 8 | 10500 nM*hr | Geometric Coefficient of Variation 58.7 |
| Part 2 Panel C MK-8189 Add-on Therapy 8 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 11 | 8540 nM*hr | Geometric Coefficient of Variation 31.2 |
| Part 2 Panel C MK-8189 Add-on Therapy 12 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 11 | 14900 nM*hr | Geometric Coefficient of Variation 58.9 |
| Part 2 Panel C MK-8189 Add-on Therapy 12 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 14 | 13200 nM*hr | Geometric Coefficient of Variation 38.5 |
| Part 2 Panel C MK-8189 Add-on Therapy 16 mg: Schizophrenic | Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC[0-24hr]) of MK-8189 in Schizophrenia Participants | Day 14 | 18700 nM*hr | Geometric Coefficient of Variation 59.4 |
Primary
Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants
Cmax was defined as the maximum concentration of MK-8189 observed in plasma. Blood samples were collected pre-dose and up to 48 hours post-dose at multiple time points to estimate Cmax following MK-8189 administration. As specified by the protocol, Cmax was analyzed by part, dose and dosing schedule. Due to differing dosing schedules, some time points were not applicable for certain arms/doses as indicated by zero participants analyzed entered in the table. Per protocol, healthy participants (Part 3) and participants receiving placebo were excluded from Cmax analysis.
Time frame: Day 1 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 24 hours post-dose; Days 4, 8, 11 pre-dose and 6, 10, 16, 24 hours post-dose; Day 14 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48 hours post-dose
Population: Schizophrenia participants who received ≥1 dose of MK-8189, complied with the protocol and had Cmax data available for Days 1, 4, 8, 11, or 14. Due to differing dosing schedules, some time points were not applicable for some arms (shown by 0 participants analyzed). Per protocol, healthy participants (Part 3) and placebo arms were excluded.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 4 | 118 nM | Geometric Coefficient of Variation 60.7 |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 1 | 70.7 nM | Geometric Coefficient of Variation 29.9 |
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 8 | 212 nM | Geometric Coefficient of Variation 52 |
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 14 | 209 nM | — |
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 11 | 285 nM | — |
| Part 1 Panel A & B MK-8189 Monotherapy 8 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 11 | 472 nM | Geometric Coefficient of Variation 40.8 |
| Part 1 Panel A & B MK-8189 Monotherapy 12 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 14 | 628 nM | Geometric Coefficient of Variation 28.5 |
| Part 2 Panel C MK-8189 Add-on Therapy 2 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 4 | 90.6 nM | Geometric Coefficient of Variation 41.7 |
| Part 2 Panel C MK-8189 Add-on Therapy 2 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 1 | 63.6 nM | Geometric Coefficient of Variation 27.5 |
| Part 2 Panel C MK-8189 Add-on Therapy 4 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 8 | 210 nM | Geometric Coefficient of Variation 29.8 |
| Part 2 Panel C MK-8189 Add-on Therapy 4 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 4 | 277 nM | Geometric Coefficient of Variation 59.7 |
| Part 2 Panel C MK-8189 Add-on Therapy 4 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 1 | 165 nM | Geometric Coefficient of Variation 39.9 |
| Part 2 Panel C MK-8189 Add-on Therapy 8 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 8 | 518 nM | Geometric Coefficient of Variation 56.5 |
| Part 2 Panel C MK-8189 Add-on Therapy 8 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 11 | 409 nM | Geometric Coefficient of Variation 28.8 |
| Part 2 Panel C MK-8189 Add-on Therapy 12 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 11 | 718 nM | Geometric Coefficient of Variation 53.4 |
| Part 2 Panel C MK-8189 Add-on Therapy 12 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 14 | 638 nM | Geometric Coefficient of Variation 34.8 |
| Part 2 Panel C MK-8189 Add-on Therapy 16 mg: Schizophrenic | Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189 in Schizophrenia Participants | Day 14 | 1050 nM | Geometric Coefficient of Variation 46.3 |
Primary
Number of Participants Experiencing an Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. The number of participants who experienced at least one AE were reported.
Time frame: Up to Day 28
Population: All participants who received as least one dose of the investigational drug. Per protocol, safety was assessed by part and dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Number of Participants Experiencing an Adverse Event (AE) | 8 Participants |
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Number of Participants Experiencing an Adverse Event (AE) | 6 Participants |
| Part 1 Panel A & B MK-8189 Monotherapy 8 mg: Schizophrenic | Number of Participants Experiencing an Adverse Event (AE) | 2 Participants |
| Part 1 Panel A & B MK-8189 Monotherapy 12 mg: Schizophrenic | Number of Participants Experiencing an Adverse Event (AE) | 6 Participants |
| Part 1 Panel A & B Placebo Monotherapy: Schizophrenic | Number of Participants Experiencing an Adverse Event (AE) | 3 Participants |
| Part 2 Panel C MK-8189 Add-on Therapy 2 mg: Schizophrenic | Number of Participants Experiencing an Adverse Event (AE) | 3 Participants |
| Part 2 Panel C MK-8189 Add-on Therapy 4 mg: Schizophrenic | Number of Participants Experiencing an Adverse Event (AE) | 6 Participants |
| Part 2 Panel C MK-8189 Add-on Therapy 8 mg: Schizophrenic | Number of Participants Experiencing an Adverse Event (AE) | 7 Participants |
| Part 2 Panel C MK-8189 Add-on Therapy 12 mg: Schizophrenic | Number of Participants Experiencing an Adverse Event (AE) | 7 Participants |
| Part 2 Panel C MK-8189 Add-on Therapy 16 mg: Schizophrenic | Number of Participants Experiencing an Adverse Event (AE) | 2 Participants |
| Part 2 Panel C Placebo Add-on Therapy: Schizophrenic | Number of Participants Experiencing an Adverse Event (AE) | 4 Participants |
| Part 3 Panel D MK-8189 Monotherapy 2 mg: Healthy | Number of Participants Experiencing an Adverse Event (AE) | 5 Participants |
| Part 3 Panel D MK-8189 Monotherapy 4 mg: Healthy | Number of Participants Experiencing an Adverse Event (AE) | 5 Participants |
| Part 3 Panel D MK-8189 Monotherapy 8 mg: Healthy | Number of Participants Experiencing an Adverse Event (AE) | 6 Participants |
| Part 3 Panel D MK-8189 Monotherapy 12 mg: Healthy | Number of Participants Experiencing an Adverse Event (AE) | 3 Participants |
| Part 3 Panel D Placebo Monotherapy: Healthy | Number of Participants Experiencing an Adverse Event (AE) | 2 Participants |
Primary
Number of Participants Who Discontinue From Study Treatment Due to an AE
An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. The number of participants who discontinued study treatment due to an AE were reported.
Time frame: Up to Day 14
Population: All participants who received as least one dose of the investigational drug. Per protocol, safety was assessed by part and dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Number of Participants Who Discontinue From Study Treatment Due to an AE | 1 Participants |
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Number of Participants Who Discontinue From Study Treatment Due to an AE | 0 Participants |
| Part 1 Panel A & B MK-8189 Monotherapy 8 mg: Schizophrenic | Number of Participants Who Discontinue From Study Treatment Due to an AE | 0 Participants |
| Part 1 Panel A & B MK-8189 Monotherapy 12 mg: Schizophrenic | Number of Participants Who Discontinue From Study Treatment Due to an AE | 1 Participants |
| Part 1 Panel A & B Placebo Monotherapy: Schizophrenic | Number of Participants Who Discontinue From Study Treatment Due to an AE | 0 Participants |
| Part 2 Panel C MK-8189 Add-on Therapy 2 mg: Schizophrenic | Number of Participants Who Discontinue From Study Treatment Due to an AE | 1 Participants |
| Part 2 Panel C MK-8189 Add-on Therapy 4 mg: Schizophrenic | Number of Participants Who Discontinue From Study Treatment Due to an AE | 0 Participants |
| Part 2 Panel C MK-8189 Add-on Therapy 8 mg: Schizophrenic | Number of Participants Who Discontinue From Study Treatment Due to an AE | 0 Participants |
| Part 2 Panel C MK-8189 Add-on Therapy 12 mg: Schizophrenic | Number of Participants Who Discontinue From Study Treatment Due to an AE | 0 Participants |
| Part 2 Panel C MK-8189 Add-on Therapy 16 mg: Schizophrenic | Number of Participants Who Discontinue From Study Treatment Due to an AE | 0 Participants |
| Part 2 Panel C Placebo Add-on Therapy: Schizophrenic | Number of Participants Who Discontinue From Study Treatment Due to an AE | 0 Participants |
| Part 3 Panel D MK-8189 Monotherapy 2 mg: Healthy | Number of Participants Who Discontinue From Study Treatment Due to an AE | 0 Participants |
| Part 3 Panel D MK-8189 Monotherapy 4 mg: Healthy | Number of Participants Who Discontinue From Study Treatment Due to an AE | 0 Participants |
| Part 3 Panel D MK-8189 Monotherapy 8 mg: Healthy | Number of Participants Who Discontinue From Study Treatment Due to an AE | 1 Participants |
| Part 3 Panel D MK-8189 Monotherapy 12 mg: Healthy | Number of Participants Who Discontinue From Study Treatment Due to an AE | 1 Participants |
| Part 3 Panel D Placebo Monotherapy: Healthy | Number of Participants Who Discontinue From Study Treatment Due to an AE | 0 Participants |
Primary
Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants
C24hr was defined as the concentration of MK-8189 observed in plasma at the 24-hour nominal sampling time after administration of MK-8189. In participants receiving MK-8189, blood samples were collected pre-dose and 24 hours post-dose to estimate C24hr following MK-8189 administration. As specified by the protocol, C24hr was analyzed by part, dose and dosing schedule. Due to differing dosing schedules, some time points were not applicable for certain arms/doses as indicated by zero participants analyzed entered in the table. Per protocol, healthy participants (Part 3) and participants receiving placebo were excluded from C24 analysis.
Time frame: Day 1, 4, 8, 11 and 14 pre-dose and 24 hours post-dose
Population: Schizophrenia participants who received ≥1 dose of MK-8189, complied with the protocol and had C24 data available for Days 1, 4, 8, 11, or 14. Due to differing dosing schedules, some time points were not applicable for some arms (shown by 0 participants analyzed). Per protocol, healthy participants (Part 3) and placebo arms were excluded.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 4 | 81.1 nM | Geometric Coefficient of Variation 94.8 |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 1 | 67.0 nM | Geometric Coefficient of Variation 31.7 |
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 8 | 183 nM | Geometric Coefficient of Variation 52.2 |
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 14 | 149 nM | — |
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 11 | 148 nM | — |
| Part 1 Panel A & B MK-8189 Monotherapy 8 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 11 | 387 nM | Geometric Coefficient of Variation 42 |
| Part 1 Panel A & B MK-8189 Monotherapy 12 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 14 | 459 nM | Geometric Coefficient of Variation 33.3 |
| Part 2 Panel C MK-8189 Add-on Therapy 2 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 4 | 80.9 nM | Geometric Coefficient of Variation 49.1 |
| Part 2 Panel C MK-8189 Add-on Therapy 2 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 1 | 60.5 nM | Geometric Coefficient of Variation 37.1 |
| Part 2 Panel C MK-8189 Add-on Therapy 4 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 8 | 174 nM | Geometric Coefficient of Variation 39.4 |
| Part 2 Panel C MK-8189 Add-on Therapy 4 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 4 | 242 nM | Geometric Coefficient of Variation 67.9 |
| Part 2 Panel C MK-8189 Add-on Therapy 4 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 1 | 161 nM | Geometric Coefficient of Variation 39.8 |
| Part 2 Panel C MK-8189 Add-on Therapy 8 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 8 | 419 nM | Geometric Coefficient of Variation 59.6 |
| Part 2 Panel C MK-8189 Add-on Therapy 8 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 11 | 321 nM | Geometric Coefficient of Variation 45.1 |
| Part 2 Panel C MK-8189 Add-on Therapy 12 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 11 | 563 nM | Geometric Coefficient of Variation 72.3 |
| Part 2 Panel C MK-8189 Add-on Therapy 12 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 14 | 517 nM | Geometric Coefficient of Variation 52 |
| Part 2 Panel C MK-8189 Add-on Therapy 16 mg: Schizophrenic | Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants | Day 14 | 655 nM | Geometric Coefficient of Variation 69 |
Primary
Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants
Tmax was defined as the time required post dose to reach a maximum plasma concentration of MK-8189. It was estimated as the actual sampling time at the highest MK-8189 plasma concentration. Blood samples were collected pre-dose and up to 48 hours post-dose at multiple time points to estimate Tmax following MK-8189 administration. As specified by the protocol, Tmax was analyzed by part, dose and dosing schedule. Due to differing dosing schedules, some time points were not applicable for certain arms/doses as indicated by zero participants analyzed entered in the table. Per protocol, healthy participants (Part 3) and participants receiving placebo were excluded from Tmax analysis.
Time frame: Day 1 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 24 hours post-dose; Days 4, 8, 11 pre-dose and 6, 10, 16, 24 hours post-dose; Day 14 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48 hours post-dose
Population: Schizophrenia participants who received ≥1 dose of MK-8189, complied with the protocol and had Tmax data available for Days 1, 4, 8, 11, or 14. Due to differing dosing schedules, some time points were not applicable for some arms (shown by 0 participants analyzed). Per protocol, healthy participants (Part 3) and placebo arms were excluded.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 4 | 10 hr |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 1 | 20 hr |
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 14 | 20 hr |
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 11 | 10 hr |
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 8 | 10 hr |
| Part 1 Panel A & B MK-8189 Monotherapy 8 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 11 | 10.03 hr |
| Part 1 Panel A & B MK-8189 Monotherapy 12 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 14 | 16 hr |
| Part 2 Panel C MK-8189 Add-on Therapy 2 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 4 | 23.83 hr |
| Part 2 Panel C MK-8189 Add-on Therapy 2 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 1 | 23.83 hr |
| Part 2 Panel C MK-8189 Add-on Therapy 4 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 8 | 16 hr |
| Part 2 Panel C MK-8189 Add-on Therapy 4 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 1 | 23.83 hr |
| Part 2 Panel C MK-8189 Add-on Therapy 4 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 4 | 8 hr |
| Part 2 Panel C MK-8189 Add-on Therapy 8 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 11 | 16 hr |
| Part 2 Panel C MK-8189 Add-on Therapy 8 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 8 | 0 hr |
| Part 2 Panel C MK-8189 Add-on Therapy 12 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 11 | 16 hr |
| Part 2 Panel C MK-8189 Add-on Therapy 12 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 14 | 12 hr |
| Part 2 Panel C MK-8189 Add-on Therapy 16 mg: Schizophrenic | Time Post-dose at Which the Maximum Plasma Concentration (Tmax) of MK-8189 Was Observed in Schizophrenia Participants | Day 14 | 8 hr |
Primary
Time Required for Plasma Concentration of MK-8189 to Decrease by Half (Apparent t1/2) in Schizophrenia Participants on Day 14
t1/2 was defined as the time required to divide the MK-8189 plasma concentration by half after reaching pseudo-equilibrium. At least three quantifiable post-Cmax, terminal phase concentrations collected were used to calculate the apparent t1/2. Blood samples were collected pre-dose and up to 48 hours post-dose at multiple time points on Day 14 to estimate t1/2 following MK-8189 administration. As specified by the protocol, t1/2 was analyzed by part, dose and dosing schedule. Due to differing dosing schedules, the Day 14 timepoint was not applicable for certain arms/doses as indicated by zero participants analyzed entered in the table. Per protocol, healthy participants (Part 3) and participants receiving placebo were excluded from t1/2 analysis.
Time frame: Day 14 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48 hours post-dose
Population: Schizophrenia participants who received ≥1 dose of MK-8189, complied with the protocol and had t1/2 data available for Day 14. Due to differing dosing schedules, some time points were not applicable for some arms/doses (indicated by zero participants analyzed). Per protocol healthy participants (Part 3) and placebo arms were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Panel A & B MK-8189 Monotherapy 4 mg: Schizophrenic | Time Required for Plasma Concentration of MK-8189 to Decrease by Half (Apparent t1/2) in Schizophrenia Participants on Day 14 | 9.14 hr | — |
| Part 1 Panel A & B MK-8189 Monotherapy 12 mg: Schizophrenic | Time Required for Plasma Concentration of MK-8189 to Decrease by Half (Apparent t1/2) in Schizophrenia Participants on Day 14 | 8.38 hr | Geometric Coefficient of Variation 37.8 |
| Part 2 Panel C MK-8189 Add-on Therapy 12 mg: Schizophrenic | Time Required for Plasma Concentration of MK-8189 to Decrease by Half (Apparent t1/2) in Schizophrenia Participants on Day 14 | 8.86 hr | Geometric Coefficient of Variation 37.4 |
| Part 2 Panel C MK-8189 Add-on Therapy 16 mg: Schizophrenic | Time Required for Plasma Concentration of MK-8189 to Decrease by Half (Apparent t1/2) in Schizophrenia Participants on Day 14 | 10.4 hr | Geometric Coefficient of Variation 43.6 |
Secondary
Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants
MMN is a response to deviant tone (stimuli) measured in EEG signals. Difference in deviant EEG waveform amplitude from standard amplitude over time indicates MMN; AUC was measured as the product of MMN amplitude and time. Schizophrenic participants show reduced response to deviant stimuli. AUC change from baseline (Day -1) to Day 13 was reported. A higher change indicates improved response to deviant stimuli. Scalp EEG signals were collected using a standard system array of 19 electrodes denoted by nomenclature of scalp placement: C3, C4, Cz, F3, F4, F7, F8, Fp1, Fp2, Fz, O1, O2, P3, P4, Pz, T3, T4, T5, T6. As specified by the protocol, MK-8189 add-on therapy schizophrenia participants (Part 2), healthy participants (Part 3), and all placebo-treated participants were excluded from MMN analyses. Per protocol, MMN analyses were planned and executed in all schizophrenia participants receiving MK-8189 monotherapy, irrespective of different dosing schedules.
Time frame: Baseline and Day 13
Population: Per protocol, MMN analyses were planned and executed in all Schizophrenia participants receiving MK-8189 monotherapy (irrespective of dosing schedule) with EEG electrode data available. Per protocol, MK-8189 add-on therapy schizophrenia participants (Part 2), healthy participants (Part 3), and all placebo-treated participants were excluded.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | C3 | -4.162 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | C4 | 2.800 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | Cz | 2.813 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | F3 | 6.277 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | F4 | 9.814 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | F7 | -0.582 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | F8 | 8.817 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | Fp1 | 8.390 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | Fp2 | 11.483 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | Fz | 7.880 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | O1 | -3.011 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | O2 | -10.261 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | P3 | -9.560 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | P4 | -9.154 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | Pz | -10.019 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | T3 | -15.594 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | T4 | -3.341 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | T5 | -19.394 µV*msec |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Area Under Curve (AUC) in Monotherapy MK-8189-treated Schizophrenia Participants | T6 | -12.686 µV*msec |
Secondary
Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants
MMN is a response to deviant tone (stimuli) measured in electroencephalogram (EEG) signals. Difference in deviant EEG waveform amplitude from standard amplitude over time indicates MMN; this difference at peak waveform is MMN peak amplitude. Schizophrenic participants show reduced response to deviant stimuli. Peak amplitude change from baseline (Day -1) to Day 13 was reported. A higher change indicates improved response to deviant stimuli. Scalp EEG signals were collected using a standard system array of 19 electrodes denoted by nomenclature of scalp placement: C3, C4, Cz, F3, F4, F7, F8, Fp1, Fp2, Fz, O1, O2, P3, P4, Pz, T3, T4, T5, T6. As specified by the protocol, MK-8189 add-on therapy schizophrenia participants (Part 2), healthy participants (Part 3) and all placebo-treated participants were excluded from MMN analyses. Per protocol, MMN analyses were planned and executed in all schizophrenia participants receiving MK-8189 monotherapy, irrespective of different dosing schedules.
Time frame: Baseline and Day 13
Population: Per protocol, MMN analyses were planned and executed in all Schizophrenia participants receiving MK-8189 monotherapy (irrespective of dosing schedule) with EEG electrode data available. Per protocol MK-8189 add-on therapy schizophrenia participants (Part 2), healthy participants (Part 3) and all placebo-treated participants were excluded.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | C3 | 0.959 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | C4 | 0.812 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | Cz | 1.170 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | F3 | 1.547 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | F4 | 1.240 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | F7 | 0.616 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | F8 | 0.488 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | Fp1 | 0.779 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | Fp2 | 1.103 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | Fz | 1.462 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | O1 | -0.099 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | O2 | -0.014 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | P3 | 0.236 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | P4 | -0.037 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | Pz | 0.599 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | T3 | 1.018 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | T4 | 0.306 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | T5 | -0.260 µV |
| Part 1 Panel A & B MK-8189 Monotherapy 2 mg: Schizophrenic | Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants | T6 | 0.178 µV |