A Safety, Tolerability, and Pharmacokinetics Study of MK-8189 in Participants With Schizophrenia and in Healthy Participants (MK-8189-007)

Phase 1

Completed

Conditions: Schizophrenia

Interventions: Drug: MK-8189
Drug: Placebo
Drug: Background AAP Therapy

Registration Number: NCT03565068

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: This 4-panel study will evaluate the safety, tolerability, pharmacokinetics (PK) and corrected QT interval (QTc) effect of MK-8189 versus placebo, as monotherapy in healthy participants (Panel A) including those of Japanese descent, as monotherapy in participants with schizophrenia (Panel B), as add-on therapy in participants with schizophrenia (Panel C), and under an alternative dosing regimen as monotherapy in participants with schizophrenia (Panel D). Analysis of QTc effect will be exploratory. There will be no hypothesis testing in this study.

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 study objectives and/or to ensure appropriate safety of the study participants. The proposed doses for each Panel may be adjusted downward based on evaluation of observed safety, tolerability, and PK data.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 75

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Panel D (Schizophrenia Participants): MK-8189 Monotherapy 8-48 mg	MK-8189	Participants with Schizophrenia will receive MK-8189 monotherapy orally QD in escalating doses from 8 mg to 48 mg, as follows: Days 1-3: 8 mg, Days 4-6: 16 mg, Days 7-9: 24 mg, Days 10-12: 36 mg, Days 13-15: 48 mg, depending on safety and tolerability.
Panel C (Schizophrenia Participants): MK-8189 Add-on Therapy 4-24 mg	MK-8189	In addition to background atypical antipsychotic (AAP) treatment, participants with Schizophrenia will receive MK-8189 add-on therapy orally QD in escalating doses from 4 mg to 24 mg, as follows: Days 1-3: 4 mg, Days 4-6: 8 mg, Days 7-9: 12 mg, Days 10-12: 16 mg, Days 13-15: 20 mg, Days 16-18: 24 mg, depending on safety and tolerability.
Panel A (Healthy Participants): MK-8189 Monotherapy 4-24 mg	MK-8189	Healthy participants will receive MK-8189 monotherapy orally once daily (QD) in escalating doses from 4 mg to 24 mg, as follows: Days 1-3: 4 mg, Days 4-6: 8 mg, Days 7-9: 12 mg, Days 10-12: 16 mg, Days 13-15: 20 mg, Days 16-18: 24 mg, depending on safety and tolerability.
Panel B (Schizophrenia Participants): MK-8189 Monotherapy 4-24 mg	MK-8189	Participants with Schizophrenia will receive MK-8189 monotherapy orally QD in escalating doses from 4 mg to 24 mg, as follows: Days 1-3: 4 mg, Days 4-6: 8 mg, Days 7-9: 12 mg, Days 10-12: 16 mg, Days 13-15: 20 mg, Days 16-18: 24 mg, depending on safety and tolerability.
Panel B (Schizophrenia Participants): Placebo Monotherapy	Placebo	Participants with Schizophrenia will receive MK-8189 monotherapy matching placebo orally QD on Days 1-18.
Panel C (Schizophrenia Participants): Placebo Add-on Therapy	Background AAP Therapy	In addition to background AAP treatment, participants with Schizophrenia will receive MK-8189 add-on therapy matching placebo orally QD on Days 1-18.
Panel A (Healthy Participants): Placebo Monotherapy	Placebo	Healthy participants will receive MK-8189 monotherapy matching placebo orally QD on Days 1-18.
Panel D (Schizophrenia Participants): Placebo Monotherapy	Placebo	Participants with Schizophrenia will receive MK-8189 monotherapy matching placebo orally QD on Days 1-15.
Panel C (Schizophrenia Participants): MK-8189 Add-on Therapy 4-24 mg	Background AAP Therapy	In addition to background atypical antipsychotic (AAP) treatment, participants with Schizophrenia will receive MK-8189 add-on therapy orally QD in escalating doses from 4 mg to 24 mg, as follows: Days 1-3: 4 mg, Days 4-6: 8 mg, Days 7-9: 12 mg, Days 10-12: 16 mg, Days 13-15: 20 mg, Days 16-18: 24 mg, depending on safety and tolerability.
Panel C (Schizophrenia Participants): Placebo Add-on Therapy	Placebo	In addition to background AAP treatment, participants with Schizophrenia will receive MK-8189 add-on therapy matching placebo orally QD on Days 1-18.

Primary Outcome Measures

Name	Time	Method
The Number of Participants Who Experienced One or More Adverse Events (AEs)	Up to ~32 days	An AE was defined as 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. Per protocol, safety was analyzed by panel and dose. The number of participants who experienced one or more AEs was reported.
The Number of Participants Who Discontinued Study Treatment Due to an AE	Up to ~18 days	An AE was defined as 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. Per protocol, safety was analyzed by panel and dose. The number of participants who discontinued study treatment due to an AE was reported.

Secondary Outcome Measures

Name	Time	Method
Apparent Volume of MK-8189 Distribution (Vd/F) on Day 18 (Panels A, B, C) and Day 15 (Panel D)	2, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose on Day 18 (Panel A, B, C) and Day 15 (Panel D)	Vd/F was the apparent volume of distribution of MK-8189 between the plasma and the rest of the body, after dose, assessed as the total volume of MK-8189 that would need to be uniformly distributed to achieve the desired plasma drug concentration. To estimate Vd/F, per protocol blood samples were collected 2, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose on Day 18 for Panels A, B, C, and on Day 15 for Panel D. Per protocol Vd/F was analyzed by panel, dose and dosing regimen. Due to differing dosing regimen, some arms/doses weren't applicable to some timepoints, shown by 0 participants analyzed in the table. Per dosing regimen, the 4 mg, 8 mg, 12 mg, 16 mg, 20 mg (Panels A, B, C), 8 mg, 16 mg, 24 mg, 36 mg (Panel D) study arms weren't applicable to the protocol-specified timepoints/days of Vd/F analysis and were excluded. GCV was reported as a percent. Per protocol placebo arms were excluded from Vd/F analysis.
Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC0-24hr) of MK-8189	Pre-dose, 2, 6, 8, 10, 12, 16, 24 hours post-dose; no pre-dose on Day 18 (Panel A, B, C), Day 15 (Panel D); Panel A, B: Days 7, 10, 13, 16, 18; Panel C: Days 9, 12, 15, 18; Panel D: Days 1, 4, 7, 10, 13, 15	AUC was a measure of MK-8189 exposure assessed as a product of drug concentration and time, using a linear mixed effects model. To estimate AUC0-24hr per protocol blood samples were collected pre-dose, 2, 6, 8, 10, 12, 16, 24 hours post-dose for Panels A, B, C, D; no pre-dose samples collected on Day 18 (Panels A, B, C), Day 15 (Panel D). Samples were collected on Days 7, 10, 13, 16, 18 for Panels A, B; Days 9, 12, 15, 18 for Panel C; Days 1, 4, 7, 10, 13, 15 for Panel D. Per protocol AUC0-24hr was analyzed by panel, dose, dosing regimen; due to differing dosing regimen some arms/doses weren't applicable to some timepoints, shown by 0 participants analyzed in the table. Per dosing regimen the 4 mg, 8 mg (Panels A, B), 4 mg (Panel C) study arms weren't applicable to the protocol-specified timepoints/days of AUC0-24hr analysis and these arms were excluded. Geometric coefficient of variation (GCV) was reported as a percent. Per protocol placebo arms were excluded from AUC0-24hr analysis.
Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189	Pre-dose, 2, 6, 8, 10, 12, 16, 24 hours post-dose; no pre-dose on Day 18 (Panel A, B, C), Day 15 (Panel D);additional 36, 48 hours post-dose on Days 18, 15; Panel A, B: Days 7, 10, 13, 16, 18; Panel C: Days 9, 12, 15, 18; Panel D:Days 1, 4, 7, 10, 13, 15	Cmax was the maximum concentration of MK-8189 observed in plasma, assessed using a linear mixed effects model. To estimate Cmax, per protocol blood samples were collected pre-dose, 2, 6, 8, 10, 12, 16, 24 hours post-dose for Panels A, B, C, D; no pre-dose samples collected on Day 18 (Panels A, B, C), Day 15 (Panel D); additional post-dose samples collected at 36, 48 hours on Days 18 and 15. Samples were collected on Days 7, 10, 13, 16, 18 for Panels A, B; Days 9, 12, 15, 18 for Panel C; Days 1, 4, 7, 10, 13, 15 for Panel D. Per protocol Cmax was analyzed by panel, dose, dosing regimen; due to differing dosing regimen some arms/doses weren't applicable to some timepoints, shown by 0 participants analyzed in the table. Per dosing regimen, the 4 mg, 8 mg (Panels A, B), 4 mg (Panel C) study arms weren't applicable to the protocol-specified timepoints/days of Cmax analysis and were excluded. GCV was reported as a percent. Per protocol placebo arms were excluded from Cmax analysis.
Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189	24 hours post-dose; Panel A, B: Days 7, 10, 13, 16, 18; Panel C: Days 9, 12, 15, 18; Panel D: Days 1, 4, 7, 10, 13, 15	C24hr was the concentration of MK-8189 observed in plasma at the 24-hour nominal sampling time after administration of MK-8189, assessed using a linear mixed effects model. To estimate C24hr, per protocol blood samples were collected 24 hours post-dose on Days 7, 10, 13, 16, 18 for Panels A, B; Days 9, 12, 15, 18 for Panel C; Days 1, 4, 7, 10, 13, 15 for Panel D. Per protocol C24hr was analyzed by panel, dose, dosing regimen; due to differing dosing regimen some arms/doses weren't applicable to some timepoints, shown by 0 participants analyzed in the table. Per dosing regimen, the 4 mg, 8 mg (Panels A, B), 4 mg (Panel C) study arms weren't applicable to the protocol-specified timepoints/days of C24hr analysis and were excluded. GCV was reported as a percent. Per protocol placebo arms were excluded from C24hr analysis.
Time Post-dose to Maximum Observed Plasma Concentration (Tmax) of MK-8189	Pre-dose, 2, 6, 8, 10, 12, 16, 24 hours post-dose; no pre-dose on Day 18 (Panel A, B, C), Day 15 (Panel D);additional 36, 48 hours post-dose on Days 18, 15; Panel A, B: Days 7, 10, 13, 16, 18; Panel C: Days 9, 12, 15, 18; Panel D:Days 1, 4, 7, 10, 13, 15	Tmax was the actual sampling time at which maximum post-dose plasma concentration of MK-8189 was observed. To estimate Tmax, per protocol blood samples were collected pre-dose, 2, 6, 8, 10, 12, 16, 24 hours post-dose for Panels A, B, C, D; no pre-dose samples collected on Day 18 (Panels A, B, C), Day 15 (Panel D); additional post-dose samples collected at 36, 48 hours on Days 18 and 15. Samples were collected on Days 7, 10, 13, 16, 18 for Panels A, B; Days 9, 12, 15, 18 for Panel C; Days 1, 4, 7, 10, 13, 15 for Panel D. Per protocol Tmax was analyzed by panel, dose, dosing regimen; due to differing dosing regimen, some arms/doses weren't applicable to some timepoints, shown by 0 participants analyzed in the table. Per dosing regimen, the 4 mg, 8 mg (Panels A, B), 4 mg (Panel C) study arms weren't applicable to the protocol-specified timepoints/days of Tmax analysis and were excluded. Per protocol placebo arms were excluded from Tmax analysis.
Apparent Total Plasma Clearance of MK-8189 (CL/F) on Day 18 (Panels A, B, C) and Day 15 (Panel D)	2, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose on Day 18 (Panel A, B, C) and Day 15 (Panel D)	CL/F was the apparent total clearance of MK-8189 in plasma over time, assessed as the rate at which MK-8189 was removed from the plasma. To estimate CL/F, per protocol blood samples were collected 2, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose on Day 18 for Panels A, B, C, and on Day 15 for Panel D. Per protocol CL/F was analyzed by panel, dose and dosing regimen. Due to differing dosing regimen, some arms/doses weren't applicable to some timepoints, shown by 0 participants analyzed in the table. Per dosing regimen, the 4 mg, 8 mg, 12 mg, 16 mg, 20 mg (Panels A, B, C), 8 mg, 16 mg, 24 mg, 36 mg (Panel D) study arms weren't applicable to the protocol-specified timepoints/days of CL/F analysis and were excluded. GCV was reported as a percent. Per protocol placebo arms were excluded from CL/F analysis.
Time Required for Plasma Concentration of MK-8189 to Decrease by Half (Apparent Terminal Half-life [t1/2]) on Day 18 (Panels A, B, C) and Day 15 (Panel D)	2, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose on Day 18 (Panel A, B, C) and Day 15 (Panel D)	t1/2 was the time required to divide the plasma concentration of MK-8189 by half after reaching pseudo-equilibrium. At least three quantifiable terminal phase concentrations collected were used to calculate t1/2. To estimate t1/2, per protocol blood samples were collected 2, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose on Day 18 for Panels A, B, C, and on Day 15 for Panel D. Per protocol t1/2 was analyzed by panel, dose and dosing regimen. Due to differing dosing regimen, some arms/doses weren't applicable to some timepoints, shown by 0 participants analyzed in the table. Per dosing regimen, the 4 mg, 8 mg, 12 mg, 16 mg, 20 mg (Panels A, B, C), 8 mg, 16 mg, 24 mg, 36 mg (Panel D) study arms weren't applicable to the protocol-specified timepoints/days of t1/2 analysis and were excluded. GCV was reported as a percent. Per protocol placebo arms were excluded from t1/2 analysis.