Safety, Tolerability, and Pharmacokinetics Study of MK-8189 in Participants With Schizophrenia and Healthy Participants (MK-8189-011)

Study Overview
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Brief Summary
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This 2-Part Randomized Clinical Study will evaluate the safety, tolerability and pharmacokinetics of alternate MK-8189 titration regimens. Part 1 will assess multiple dose once-daily titration regimens of MK-8189 in young adult participants with schizophrenia. Part 2 will assess multiple once-daily doses of MK-8189 in elderly participants with schizophrenia and healthy elderly participants.

Official Title
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A 2-Part Randomized Clinical Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Alternate MK-8189 Titration Regimens in Young Adult Participants With Schizophrenia and to Evaluate the Safety, Tolerability and Pharmacokinetics of MK-8189 in Elderly Participants With Schizophrenia and Healthy Elderly

Conditions
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Schizophrenia

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a body mass index (BMI) ≤40 kg/m2 Has no clinically significant abnormality on 12-lead safety electrocardiogram (ECG) performed at the prestudy (screening) visit and/or prior to randomization Has a normal resting blood pressure (BP: systolic BP is ≥90 millimeter of mercury [mmHg] and ≤140 mmHg; diastolic BP is ≥60 mmHg and ≤90 mmHg) and normal resting heart rate (≥45 beats per minute [bpm] and ≤100 bpm) in the semirecumbent position at the prestudy (screening) visit and/or prior to randomization. Repeat evaluations may be done if the values for a participant are, per investigator discretion, minimally outside the designated range. Participants may be included if values are outside the normal range but considered not clinically significant per investigator discretion Participants with schizophrenia only: Meets diagnostic criteria for schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria with the onset of the first episode being no less than 2 years prior to screening and monotherapy with antipsychotics for treatment should be indicated Participants with schizophrenia only: Has a total Brief Psychiatric Rating Scale (BPRS) score of <48 with a BPRS score <4 for #10 (hostility) and #14 (uncooperativeness) at the screening visit Participants with schizophrenia only: Is in the nonacute phase of their illness and clinically stable for 3 months prior to screening as demonstrated by the following: 1) no clinically significant change in dose of prescribed antipsychotic medication, or clinically significant change in antipsychotic medication to treat symptoms of schizophrenia for 2 months prior to screening 2) no increase in level of psychiatric care due to worsening of symptoms of schizophrenia for 3 months prior to screening Participants with schizophrenia only: Has a history of receiving and tolerating antipsychotic medication within the usual dose range employed for schizophrenia Participants with schizophrenia only: Has a stable living situation Participants with hypothyroidism, diabetes, high BP, chronic respiratory conditions or other mild forms of these medical conditions could be considered as candidates for study enrollment if their condition is stable Has regular bowel movements Participants with schizophrenia only: Is able to discontinue the use of all antipsychotic medication at least 5 days prior to the start of the treatment period and during the study period Female participants are not pregnant and not breastfeeding, and are not a woman of childbearing potential (WOCBP) or are a WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 14 days after the last dose of study intervention Exclusion Criteria: Is a WOCBP who has a positive urine pregnancy test within 48 hours before the first dose of study intervention Participants with schizophrenia only: Has evidence or history of a primary DSM-5 axis I psychiatric diagnosis other than schizophrenia or schizoaffective disorder per the allowed DSM-5 criteria within 1 month of screening Has evidence or history of a primary DSM-5 axis I psychiatric diagnosis other than schizophrenia or schizoaffective disorder per the allowed DSM-5 criteria within 1 month of screening Has evidence or history of mental retardation, borderline personality disorder, anxiety disorder, or organic brain syndrome Has a history of neuroleptic malignant syndrome or moderate to severe tardive dyskinesia Has a substance-induced psychotic disorder or behavioral disturbance thought to be due to substance abuse Has a DSM-5 defined substance use disorder within 3 months of screening Has a history of seizure disorder beyond childhood or is receiving treatment with any anticonvulsant to prevent seizures Has an untreated or uncompensated clinically significant renal, endocrine, hepatic, respiratory, gastrointestinal, psychiatric, neurologic, cardiovascular, hematological, immunological or cerebrovascular disease, malignancy, allergic disease or other chronic and/or degenerative process at screening Has any clinically significant abnormal laboratory, vital sign (VS), physical examination, or 12-lead safety ECG findings at screening or changes from baseline parameters or, in the opinion of the investigator, would make the participant inappropriate for entry into this study Has a history of cancer with following exceptions: 1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or; 2) Other malignancies which have been successfully treated with appropriate follow up and therefore unlikely to recur for the duration of the study, in the opinion of the investigator and with agreement of the Sponsor Has a clinically significant history or presence of sick sinus syndrome, first, second, or third-degree AV block, myocardial infarction, pulmonary congestion, cardiac arrhythmia, prolonged corrected QT (QTc) interval, or conduction abnormalities Has history of repeated or frequent syncope, vasovagal episodes, or epileptic seizures Has a family history of sudden death Has a history of any illness that, in the opinion of the study investigator, might confound the results of the study or poses an additional risk to the participant by their participation in the study For Part 2 participants only: Participant has an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 based on the modification of diet in renal disease (MDRD). Participants who have an eGFR or measured creatinine clearance of up to10% below of either 60 milliliter/minute [mL/min] (for creatinine clearance) or 60 mL/min/1.73m2 (for eGFR) may be enrolled in the study at the discretion of the investigator Has a history of significant multiple and/or severe allergies or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food Is positive for Hepatitis B surface antigen, Hepatitis C antibodies or HIV Had major surgery, donated or lost 1 unit of blood within 4 weeks prior to the prestudy (screening) visit Healthy participants only: Is mentally or legally incapacitated, has significant emotional problems at the time of prestudy (screening) visit or expected during the conduct of the study or has a history of clinically significant psychiatric disorder of the last 5 years (participants who have had situational depression may be enrolled in the study at investigator's discretion) Participants with schizophrenia only: Is at imminent risk of self-harm, based on clinical interview and responses on the Columbia-Suicide Severity Rating Scale (C-SSRS), or of harm to others in the opinion of the investigator Healthy participants only: Is at imminent risk of self-harm, based on clinical interview and responses on the CSSRS, or of harm to others in the opinion of the investigator. Participants must be excluded if they report suicidal ideation with intent, with or without a plan or in the past 5 years or suicidal behavior in their lifetime Has received treatment with clozapine for schizophrenia or treatment with monoamine oxidase inhibitors within 3 months of screening or cariprazine within 2 months of screening Has received a parenteral depot antipsychotic medication within 3 months of screening Is unable to refrain from the use of co-medication with a moderate or strong inhibiting or inducing effect on cytochrome (CYP3A) and/or cytochrome (CYP2C9) beginning approximately 2 weeks or 5 half-lives, whichever is longer, prior to administration of the initial dose of trial drug and throughout the trial or is unable to refrain from the use of sensitive substrates of cytochrome (CYP2B6) Has participated in another investigational study within 4 weeks (or 5 half-lives, whichever is greater) prior to the prestudy (screening) visit Has been in incarceration or imprisonment within three months prior to screening Is a current smoker (healthy participants only) or is a smoker (participants with schizophrenia only) that does not agree to follow the smoking restrictions as defined by the clinical research unit (CRU) Consumes greater than 3 glasses of alcoholic beverages per day. Participants who consume 4 glasses of alcoholic beverages per day may be enrolled at the discretion of the investigator Consumes excessive amounts, defined as greater than 6 servings of caffeinated beverages per day Is a regular user of cannabis, any illicit drugs or has a history of drug abuse within approximately 3 years Presents any concern by the investigator regarding safe participation in the study or for any other reason the investigator considers the participant inappropriate for participation in the study Is or has an immediate family member who is investigational site or Sponsor staff directly involved with this study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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) MK-8189<br>Young adult participants with schizophrenia receive MK-8189 titrated from 16 mg to 24 mg once daily (QD), orally, over a course of 7-day treatment. | Drug: MK-8189<br>* MK-8189, oral, 4 mg and/or 12 mg tablets for a total daily dose of 8, 16 or 24 mg QD according to randomization<br>|
| Experimental: Part 1 (Panel B) MK-8189<br>Young adult participants with schizophrenia receive MK-8189 titrated up to 24 mg QD, orally, over a course of 7-day treatment period with starting doses based on safety and tolerability of previous starting dose in previous panel. | Drug: MK-8189<br>* MK-8189, oral, 4 mg and/or 12 mg tablets for a total daily dose of 8, 16 or 24 mg QD according to randomization<br>|
| Experimental: Part 1 (Panel C) MK-8189<br>Young adult participants with schizophrenia receive MK-8189 titrated from 8 mg to 24 mg QD, orally, over a course of 7-day treatment period with starting doses based on safety and tolerability of previous starting dose in previous panels. | Drug: MK-8189<br>* MK-8189, oral, 4 mg and/or 12 mg tablets for a total daily dose of 8, 16 or 24 mg QD according to randomization<br>|
| Experimental: Part 2 (Panel D) MK-8189<br>Elderly adult participants with schizophrenia receive MK-8189 titrated from 8 mg to 24 mg QD, orally, over the course of a 13-day treatment period with starting doses based on safety and tolerability of previous starting dose in previous panels. | Drug: MK-8189<br>* MK-8189, oral, 4 mg and/or 12 mg tablets for a total daily dose of 8, 16 or 24 mg QD according to randomization<br>|
| Experimental: Part 2 (Panel E) MK-8189<br>Elderly adult participants with schizophrenia receive MK-8189 titrated from 16 mg to 24 mg QD, orally, over the course of 10-day treatment period with starting doses based on safety and tolerability of previous starting dose in previous panels. | Drug: MK-8189<br>* MK-8189, oral, 4 mg and/or 12 mg tablets for a total daily dose of 8, 16 or 24 mg QD according to randomization<br>|
| Experimental: Part 2 (Panel F) MK-8189<br>Healthy elderly adult participants receive MK-8189 titrated from 8 mg to 24 mg QD, orally, over the course of a 13-day treatment period with starting doses based on safety and tolerability of previous starting dose in previous panels. | Drug: MK-8189<br>* MK-8189, oral, 4 mg and/or 12 mg tablets for a total daily dose of 8, 16 or 24 mg QD according to randomization<br>|
| Experimental: Part 2 (Panel G) MK-8189<br>Healthy elderly adult participants receive MK-8189 titrated from 16 mg to 24 mg QD, orally, over the course of 10-day treatment period with starting doses based on safety and tolerability of previous starting dose in previous panels. | Drug: MK-8189<br>* MK-8189, oral, 4 mg and/or 12 mg tablets for a total daily dose of 8, 16 or 24 mg QD according to randomization<br>|
| Placebo Comparator: Part 1 (Panels A, B, C) Placebo<br>Oral tablets of dose-matched placebo to total daily dose of MK-8189. | Drug: Placebo<br>* Oral tablets of dose-matched placebo to MK-8189 according to randomization<br>|
| Placebo Comparator: Part 2 (Panels D, E, F, G) Placebo<br>Oral tablets of dose-matched placebo to total daily dose of MK-8189. | Drug: Placebo<br>* Oral tablets of dose-matched placebo to MK-8189 according to randomization<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1 & 2: Number of Participants Who Experienced an Adverse Event (AE) | The number of participants experiencing an AE will be assessed. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to approximately 27 days | 
| Part 1 & 2: Number of Participants Discontinuing Study Treatment Due to an AE | The number of participants discontinuing study treatment due to an AE will be assessed. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to approximately 27 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8189 | AUC0-24hr is defined as the area under concentration-time curve from 0 to 24 hours. Blood samples taken at predose and up to 24 hours postdose to determine the AUC0-24hr of MK-8189. | Panels A, B, C: Predose and selected time points postdose on Days 1 and 7. Additional collections for Panel A on Day 4 and Panel C on Days 2 and 3 | 
| Part 1: Maximum Concentration (Cmax) of MK-8189 | Cmax is defined as the maximum concentration of MK-8189 observed in plasma. Blood samples taken at predose and at specified times postdose to determine the Cmax of MK-8189. | Panels A, B, C: Predose and selected time points postdose on Days 1 and 7. Additional collections for Panel A on Day 4 and Panel C on Days 2 and 3 | 
| Part 1: Concentration of MK-8189 at 24 Hours (C24hr) postdose | C24hr is defined as the concentration of MK-8189 observed in plasma at 24 hours. Blood samples taken at predose and up to 24 hours postdose to determine the C24hr of MK-8189. | Panels A, B, C: Predose and up to 24 hours postdose on Days 1 and 7. Additional collections for Panel A on Day 4 and Panel C on Days 2 and 3 | 
| Part 1: Time to Cmax (Tmax) of MK-8189 | Tmax is defined as the time of maximum concentration of MK-8189 observed in plasma. Blood samples taken at predose and at specified times postdose to determine the Tmax of MK-8189. | Panels A, B, C: Predose and selected time points postdose on Days 1 and 7. Additional collections for Panel A on Day 4 and Panel C on Days 2 and 3 | 
| Part 1: Clearance (CL) of MK-8189 | Blood samples taken at predose and at specified times postdose to determine the CL of MK-8189. | Panels A, B, C: Predose and selected time points postdose on Day 7 | 
| Part 1: Volume of Distribution (Vd) of MK-8189 | Blood samples taken at predose and at specified times postdose to determine the Vd of MK-8189. | Panels A, B, C: Predose and selected time points postdose on Day 7 | 
| Part 1: Apparent Terminal Half-life (t1/2) of MK-8189 | Blood samples taken at predose and at specified times postdose to determine the t1/2 of MK-8189. | Panels A, B, C: Predose and selected time points postdose on Day 7 | 
| Part 2: Area Under the Concentration Time-curve From Hour 0 to 24 Hours (AUC0-24hr) of MK-8189 | AUC0-24hr is defined as the area under concentration-time curve from 0 to 24 hours. Blood samples taken at predose and up to 24 hours postdose to determine the AUC0-24hr of MK-8189. | Panels D, F: Predose and selected time points postdose on Days 1, 4, 7 and 13; Panels E, G: Predose and selected time points postdose on Days 1, 4, and 10 | 
| Part 2: Maximum Concentration (Cmax) of MK-8189 | Cmax is defined as the maximum concentration of MK-8189 observed in plasma. Blood samples taken at predose and at specified times postdose to determine the Cmax of MK-8189. | Panels D, F: Predose and selected time points postdose on Days 1, 4, 7 and 13; Panels E, G: Predose and selected time points postdose on Days 1, 4, and 10 | 
| Part 2: Concentration of MK-8189 at 24 Hours (C24hr) postdose | C24hr is defined as the concentration of MK-8189 observed in plasma at 24 hours. Blood samples taken at predose and up to 24 hours postdose to determine the C24hr of MK-8189. | Panels D, F: Predose and up to 24 hours postdose on Days 1, 4, 7 and 13; Panels E, G: Predose and up to 24 hours postdose on Days 1, 4, and 10 | 
| Part 2: Time to Cmax (Tmax) of MK-8189 | Tmax is defined as the time of maximum concentration of MK-8189 observed in plasma. Blood samples taken at predose and at specified times postdose to determine the Tmax of MK-8189. | Panels D, F: Predose and selected time points postdose on Days 1, 4, 7 and 13; Panels E, G: Predose and selected time points postdose on Days 1, 4, and 10 | 
| Part 2: Clearance (CL) of MK-8189 | Blood samples taken at predose and at specified times postdose to determine the CL of MK-8189. | Panels D, F: Predose and selected time points postdose on Day 13; Panels E, G: Predose and selected time points postdose on Day 10 | 
| Part 2: Volume of Distribution (Vd) of MK-8189 | Blood samples taken at predose and at specified times postdose to determine the Vd of MK-8189. | Panels D, F: Predose and selected time points postdose on Day 13; Panels E, G: Predose and selected time points postdose on Day 10 | 
| Part 2: Apparent Terminal Half-life (t1/2) of MK-8189 | Blood samples taken at predose and at specified times postdose to determine the t1/2 of MK-8189. | Panels D, F: Predose and selected time points postdose on Day 13; Panels E, G: Predose and selected time points postdose on Day 10 |