MK-8189 Multiple Dose Study in Healthy Volunteers and Schizophrenia Participants (MK-8189-003)

Study Overview
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Brief Summary
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This 3-part dose titration study will assess MK-8189 safety, tolerability, pharmacokinetics (PK), and central nervous system activity. Part 1 (Panels A and B) will assess MK-8189 administered as monotherapy in participants with schizophrenia. Part 2 (Panel C) will assess MK-8189 administered as add-on to atypical antipsychotic treatment in participants with schizophrenia. Part 3 (Panel D) will assess monotherapy with MK-8189 in healthy participants, including those of Japanese descent. The primary hypothesis is that there is at least one dose of MK-8189 that is generally safe and well-tolerated which will have the desired PK parameters in participants with schizophrenia.

Detailed Description
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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.

Official Title
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A Multiple Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-8189 in Healthy Volunteers and in Schizophrenia Patients

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: MK-8189
* Drug: Placebo
* Drug: Base Monotherapy


Participation Criteria
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Eligibility Criteria
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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 Exclusion Criteria: EXCLUSION CRITERIA FOR SCHIZOPHRENIA PARTICIPANTS DSM-IV axis I psychiatric diagnosis other than schizophrenia or schizoaffective disorder within one month of screening Has evidence or history of mental retardation, borderline personality disorder, anxiety disorder, or organic brain syndrome History of neuroleptic malignant syndrome or moderate to severe tardive dyskinesia Untreated or uncompensated clinically significant renal, endocrine, hepatic, respiratory, gastrointestinal, psychiatric, neurologic, cardiovascular, hematological, immunological or cerebrovascular disease, malignance, allergic disease or other chronic and/or degenerative process at screening Has a history of cancer (malignancy) with certain exceptions Treatment with clozapine for schizophrenia or treatment with monoamine oxidase inhibitors within 3 months of screening Received a parenteral depot antipsychotic medication within 3 months of screening Participated in another investigational study within 4 weeks, prior to screening EXCLUSION CRITERIA FOR HEALTHY PARTICIPANTS History of clinically significant endocrine, gastrointestinal, cardiovascular (including hypertension, angina, coronary artery disease, valvular disease, heart rate or rhythm abnormalities), hematological, hepatic, immunological, renal, respiratory, genitourinary or major neurological (including stroke and chronic seizures) abnormalities or diseases Mentally or legally incapacitated History of clinically diagnosed depression, anxiety disorder, or any history of psychiatric disorders having required drug treatment or hospitalization History of cancer (malignancy) Unable to refrain from or anticipates the use of any medication, including prescription and non-prescription drugs or herbal remedies throughout the trial Participated in another investigational study within 4 weeks, prior to screening

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1 Panel A & B MK-8189 Monotherapy 2-40 mg: Schizophrenic<br>Participants with schizophrenia will receive monotherapy of MK-8189 in escalating doses starting at 2 mg once daily (QD) up to 40 mg QD, depending on safety and tolerability | Drug: MK-8189<br>* 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<br>|
| Experimental: Part 2 Panel C MK-8189 Add-on Therapy 2-20 mg: Schizophrenic<br>Participants with schizophrenia will receive add-on therapy of MK-8189 in escalating doses starting at 2 mg QD up to 20 mg QD, depending on safety and tolerability | Drug: MK-8189<br>* 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<br>Drug: Base Monotherapy<br>* 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.<br>|
| Experimental: Part 2 Panel C MK-8189 Add-on Therapy 4-20 mg: Schizophrenic<br>Participants with schizophrenia will receive add-on therapy of MK-8189 in escalating doses starting at 4 mg QD up to 20 mg QD, depending on safety and tolerability | Drug: MK-8189<br>* 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<br>Drug: Base Monotherapy<br>* 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.<br>|
| Experimental: Part 3 Panel D MK-8189 Monotherapy 2-16 mg: Healthy<br>Healthy participants will receive monotherapy of MK-8189 in escalating doses starting at 2 mg QD up to 16 mg QD, depending on safety and tolerability | Drug: MK-8189<br>* 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<br>|
| Placebo Comparator: Part 1 Panel A & B Placebo Monotherapy: Schizophrenic<br>Participants with schizophrenia will receive dose-matched placebo to MK-8189 monotherapy | Drug: Placebo<br>* Placebo matching oral 2 mg and/or 10 mg MK-8189 tablets, taken QD<br>|
| Placebo Comparator: Part 2 Panel C Placebo Add-on Therapy: Schizophrenic<br>Participants with schizophrenia will receive dose-matched placebo to MK-8189 add-on therapy | Drug: Placebo<br>* Placebo matching oral 2 mg and/or 10 mg MK-8189 tablets, taken QD<br>Drug: Base Monotherapy<br>* 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.<br>|
| Placebo Comparator: Part 3 Panel D Placebo Monotherapy: Healthy<br>Healthy participants will receive dose-matched placebo to MK-8189 monotherapy | Drug: Placebo<br>* Placebo matching oral 2 mg and/or 10 mg MK-8189 tablets, taken QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 1, 4, 8, 11 and 14 pre-dose and 24 hours post-dose | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | 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 | 
| 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. | Day 14 pre-dose and 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48 hours post-dose | 
| 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. | Up to Day 28 | 
| 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. | Up to Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline and Day 13 | 
| 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. | Baseline and Day 13 |