A Safety, Tolerability, and Pharmacokinetics Study of MK-8189 in Participants With Schizophrenia and in Healthy Participants (MK-8189-007)
Condition: Schizophrenia
MeSH terms: Schizophrenia
Intervention: MK-8189; Placebo; Background AAP Therapy
Intervention description: 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.; MK-8189 dose-matching placebo tablets will be administered orally QD.; 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.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 75.0
Sex: All
Minimum age: 18 Years
Maximum age: 60 Years
Healthy volunteers: Accepts Healthy Volunteers

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.
    

Eligibility criteria:

        Inclusion Criteria

        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.

        Exclusion Criteria

        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.

          -  Has a history of seizure disorder beyond childhood or is receiving treatment with any
             anticonvulsant to prevent seizures.

          -  Is at imminent risk of self-harm, based on clinical interview and responses on the
             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 2 months or suicidal behavior in the past 6 months.

          -  Has received treatment with clozapine for schizophrenia or treatment with monoamine
             oxidase inhibitors within 3 months of screening. For Panel C participants, has
             received a total daily dose of risperidone > 6 mg.

          -  Is unable to refrain from the use of co-medication with a moderate or strong
             inhibiting or inducing effect on cytochrome P450 (CYP) 3A (CYP3A) and/or 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 CYP2B6. Unable to refrain from
             cyclic hormone replacement therapy. There may be certain medications that are
             permitted

          -  Has received a parenteral depot antipsychotic medication within 3 months of pre-trial
             (screening).

        Panels A, B, C, and D

          -  Is a woman of childbearing potential (WOCBP) who has a positive serum pregnancy test
             at the screening visit or a positive urine pregnancy test within 48 hours before the
             first dose of study intervention. If the urine test is positive or cannot be confirmed
             as negative, a serum pregnancy test will be required.

          -  Has a history of cancer (malignancy). Exceptions include: (1) Participants with
             adequately treated nonmelanomatous skin carcinoma or carcinoma in situ of the cervix
             may participate in the study; (2) Participants with other malignancies which have been
             successfully treated ≥10 years prior to the prestudy (screening) visit where, in the
             judgment of both the investigator and treating physician, appropriate follow-up has
             revealed no evidence of recurrence from the time of treatment through the time of the
             prestudy (screening) visit (except those cancers identified at the beginning of this
             exclusion criteria); or (3) Participants, who, in the opinion of the study
             investigator, are highly unlikely to sustain a recurrence for the duration of the
             study.

          -  Has a clinically significant history or presence of sick sinus syndrome, first,
             second, or third degree atrioventricular (AV) block, myocardial infarction, pulmonary
             congestion, cardiac arrhythmia, prolonged 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.

          -  Has a history of significant multiple and/or severe allergies (e.g., food, drug, latex
             allergy), or has had an anaphylactic reaction or significant intolerability (i.e.,
             systemic allergic reaction) to prescription or non-prescription drugs or food.

          -  Has Hepatitis B, Hepatitis C or Human Immunodeficiency Virus (HIV) infection.

          -  Had major surgery, donated or lost 1 unit of blood (approximately 500 mL) within 4
             weeks prior to the prestudy (screening) visit.

          -  Has participated in another investigational study within 4 weeks (or 5 half-lives,
             whichever is greater) prior to the prestudy (screening) visit. The window will be
             derived from the date of the last visit in the previous study.

          -  Has history or presence of risk factors for Torsade de Pointes (e.g., cardiac disease,
             heart failure, hypokalaemia or hypomagnesaemia, hypertrophy, cardiomyopathy, or family
             history of long QT syndrome). Plasma calcium must be within normal limits at screening
             and serum calcium must be within normal limits prior to dosing.

          -  Is under the age of legal consent.

          -  Has been in incarceration or imprisonment within 3 months prior to screening.

          -  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 (1 serving is
             approximately equivalent to 120 mg of caffeine) of coffee, tea, cola, energy drinks,
             or other caffeinated beverages per day.

          -  Is a regular user of cannabis, any illicit drugs or has a history of drug (including
             alcohol) abuse within approximately 3 years.