A Multiple Dose Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-8189 in Healthy Volunteers and in Schizophrenia Patients
Overview
- Phase
- Phase 1
- Intervention
- MK-8189
- Conditions
- Schizophrenia
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 55
- Primary Endpoint
- Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants
- Status
- Completed
- Last Updated
- 6 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
Part 2 Panel C MK-8189 Add-on Therapy 4-20 mg: Schizophrenic
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
Intervention: MK-8189
Part 1 Panel A & B MK-8189 Monotherapy 2-40 mg: Schizophrenic
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
Intervention: MK-8189
Part 2 Panel C MK-8189 Add-on Therapy 2-20 mg: Schizophrenic
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
Intervention: MK-8189
Part 2 Panel C MK-8189 Add-on Therapy 2-20 mg: Schizophrenic
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
Intervention: Base Monotherapy
Part 2 Panel C MK-8189 Add-on Therapy 4-20 mg: Schizophrenic
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
Intervention: Base Monotherapy
Part 3 Panel D MK-8189 Monotherapy 2-16 mg: Healthy
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
Intervention: MK-8189
Part 1 Panel A & B Placebo Monotherapy: Schizophrenic
Participants with schizophrenia will receive dose-matched placebo to MK-8189 monotherapy
Intervention: Placebo
Part 2 Panel C Placebo Add-on Therapy: Schizophrenic
Participants with schizophrenia will receive dose-matched placebo to MK-8189 add-on therapy
Intervention: Placebo
Part 2 Panel C Placebo Add-on Therapy: Schizophrenic
Participants with schizophrenia will receive dose-matched placebo to MK-8189 add-on therapy
Intervention: Base Monotherapy
Part 3 Panel D Placebo Monotherapy: Healthy
Healthy participants will receive dose-matched placebo to MK-8189 monotherapy
Intervention: Placebo
Outcomes
Primary Outcomes
Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189 in Schizophrenia Participants
Time Frame: 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
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
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
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
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
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
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
Time Frame: 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)
Time Frame: 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
Time Frame: 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 Outcomes
- Change From Baseline at Day 13 in Mismatched Negativity (MMN) Peak Amplitude in Monotherapy MK-8189-treated Schizophrenia Participants(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(Baseline and Day 13)