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

NCT03565068 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 8189-007MK-8189-007
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 1

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.

Conditions

Schizophrenia

Outcome Measures

Primary Outcomes (2)

• The Number of Participants Who Experienced One or More Adverse Events (AEs)

  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.

  Up to ~32 days

• The Number of Participants Who Discontinued Study Treatment Due to an AE

  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.

  Up to ~18 days

Secondary Outcomes (7)

• 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

• 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

• 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

• 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

• 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)

Study Arms (8)

Panel A (Healthy Participants): MK-8189 Monotherapy 4-24 mg

EXPERIMENTAL

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.

Drug: MK-8189

Panel A (Healthy Participants): Placebo Monotherapy

PLACEBO COMPARATOR

Healthy participants will receive MK-8189 monotherapy matching placebo orally QD on Days 1-18.

Drug: Placebo

Panel B (Schizophrenia Participants): MK-8189 Monotherapy 4-24 mg

EXPERIMENTAL

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.

Drug: MK-8189

Panel B (Schizophrenia Participants): Placebo Monotherapy

PLACEBO COMPARATOR

Participants with Schizophrenia will receive MK-8189 monotherapy matching placebo orally QD on Days 1-18.

Drug: Placebo

Panel C (Schizophrenia Participants): MK-8189 Add-on Therapy 4-24 mg

EXPERIMENTAL

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.

Drug: MK-8189; Drug: Background AAP Therapy

Panel C (Schizophrenia Participants): Placebo Add-on Therapy

PLACEBO COMPARATOR

In addition to background AAP treatment, participants with Schizophrenia will receive MK-8189 add-on therapy matching placebo orally QD on Days 1-18.

Drug: Placebo; Drug: Background AAP Therapy

Panel D (Schizophrenia Participants): MK-8189 Monotherapy 8-48 mg

EXPERIMENTAL

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.

Drug: MK-8189

Panel D (Schizophrenia Participants): Placebo Monotherapy

PLACEBO COMPARATOR

Participants with Schizophrenia will receive MK-8189 monotherapy matching placebo orally QD on Days 1-15.

Drug: Placebo

Interventions

MK-8189 DRUG

MK-8189 4 mg tablet(s) will be administered orally QD for a total daily dose of 4 mg, 8 mg, 12 mg, 16 mg, 20 mg, 24 mg, 36 mg or 48 mg.

Panel A (Healthy Participants): MK-8189 Monotherapy 4-24 mg; Panel B (Schizophrenia Participants): MK-8189 Monotherapy 4-24 mg; Panel C (Schizophrenia Participants): MK-8189 Add-on Therapy 4-24 mg; Panel D (Schizophrenia Participants): MK-8189 Monotherapy 8-48 mg

Placebo DRUG

MK-8189 dose-matching placebo tablets will be administered orally QD.

Panel A (Healthy Participants): Placebo Monotherapy; Panel B (Schizophrenia Participants): Placebo Monotherapy; Panel C (Schizophrenia Participants): Placebo Add-on Therapy; Panel D (Schizophrenia Participants): Placebo Monotherapy

Background AAP Therapy DRUG

Participants with schizophrenia in Panel C will be on background therapy with an AAP medication (e.g., olanzapine, quetiapine, paliperidone, asenapine, iloperidone, aripirprazole, lurasidone, risperidone \[not to exceed daily dose of 6 mg\], or ziprasidone) throughout the study. Participants should be on a stable and well tolerated treatment regimen for at least 2 months prior to screening. NOTE: clozapine is not allowed.

Panel C (Schizophrenia Participants): MK-8189 Add-on Therapy 4-24 mg; Panel C (Schizophrenia Participants): Placebo Add-on Therapy

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Panel A (Healthy Participants)
• \- If participant is of Japanese descent, both biological parents and all biological grandparents must be born in Japan.
• Panels B and D (Participants with Schizophrenia; MK-8189 or Placebo Monotherapy / 15-Day Titration Monotherapy) - 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.
• Panels B, C, and D (Participants with Schizophrenia; MK-8189 or Placebo Monotherapy / Add-on Therapy / 15-Day Titration Monotherapy)
• Meets diagnostic criteria for schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders (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.
• Is in the non-acute phase of their illness and clinically stable for 3 months prior to screening as demonstrated by: a.) 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; b.) no increase in level of psychiatric care due to worsening of symptoms of schizophrenia for 3 months prior to screening.
• Has a history of receiving and tolerating antipsychotic medication within the usual dose range employed for schizophrenia.
• Has a stable living situation in which the participant or a contact person can be reached by the investigator if there is a need for follow up.
• 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 co-medication during the study.
• Has regular bowel movements.
• Panels A, B, C, and D
• \- A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a woman of childbearing potential (WOCBP)
• Is a WOCBP and using a contraceptive method that is highly effective, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis), during the intervention period and for at least 14 days after the last dose of study intervention.

You may not qualify if:

• Panel A (Healthy Participants)
• Has a history of clinically diagnosed depression, anxiety disorder, or any history of psychiatric disorders having required drug treatment or hospitalization. Participants who have had situational depression more than 5 years before the start of the study may be enrolled in the study at the discretion of the investigator.
• Has a history of stroke, chronic seizures, or major neurological disorder.
• Has a history of dystonic reaction to antipsychotic, anti-emetic or related medication.
• 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. Participants must be excluded if they report suicidal ideation with intent, with or without a plan or method (e.g., positive response to item 4 or 5 in assessment of suicidal ideation on the C-SSRS) in the past 5 years or suicidal behavior in their lifetime.
• Has a history of clinically significant endocrine, gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological (including stroke and chronic seizures) abnormalities or diseases. Participants with a remote history of uncomplicated medical events may be enrolled in the study at the discretion of the investigator.
• Is mentally or legally incapacitated, 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 the discretion of the investigator.
• Is unable to refrain from or anticipates the use of any medication, including prescription and nonprescription drugs or herbal remedies, beginning approximately 2 weeks (or 5 half-lives) prior to administration of the initial dose of study drug, throughout the study (including washout intervals between treatment periods), until the poststudy visit.
• Is a smoker and/or has used nicotine or nicotine-containing products (e.g., nicotine patch and electronic cigarette) within 3 months of screening.
• Panels B, C, and D (Participants with Schizophrenia; MK-8189 or Placebo Monotherapy / Add-on Therapy / 15-Day Titration Monotherapy)
• 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 (TD).
• Has a substance-induced psychotic disorder or behavioral disturbance thought to be due to substance abuse.
• Has a DSM-5 defined substance abuse or dependence disorder (excluding nicotine and caffeine) within three months of screening.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (1)

California Clinical Trials ( Site 0001)

Glendale, California, 91206, United States

Location

MeSH Terms

Conditions

Schizophrenia

Interventions

MK-8189

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 1, 2018
• First Posted: June 21, 2018
• Study Start: June 20, 2018
• Primary Completion: April 3, 2020
• Study Completion: April 3, 2020
• Last Updated: March 29, 2021
• Results First Posted: March 29, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will share

Locations

US (1)