Clinical trial NCT03565068: A Safety, Tolerability, and Pharmacokinetics Study of MK-8189 in Participants With Schizophrenia and in Healthy Participants (MK-8189-007)
Official title: A Multiple-dose Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and QTc Effect of MK-8189 in Participants With Schizophrenia and Healthy Participants.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Schizophrenia
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2018-06-21
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: The Number of Participants Who Experienced One or More Adverse Events (AEs)
timeFrame: Up to ~32 days
measure: The Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to ~18 days
Secondary outcomes:
measure: Area Under the Plasma-concentration Curve at Zero to 24 Hours Post-dose (AUC0-24hr) of MK-8189
timeFrame: 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
measure: Maximum Observed Post-dose Plasma Concentration (Cmax) of MK-8189
timeFrame: 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
measure: Plasma Concentration at 24 Hours Post-dose (C24hr) of MK-8189
timeFrame: 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
measure: Time Post-dose to Maximum Observed Plasma Concentration (Tmax) of MK-8189
timeFrame: 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
measure: Apparent Total Plasma Clearance of MK-8189 (CL/F) on Day 18 (Panels A, B, C) and Day 15 (Panel D)
timeFrame: 2, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose on Day 18 (Panel A, B, C) and Day 15 (Panel D)
measure: Apparent Volume of MK-8189 Distribution (Vd/F) on Day 18 (Panels A, B, C) and Day 15 (Panel D)
timeFrame: 2, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose on Day 18 (Panel A, B, C) and Day 15 (Panel D)
measure: 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)
timeFrame: 2, 6, 8, 10, 12, 16, 24, 36, 48 hours post-dose on Day 18 (Panel A, B, C) and Day 15 (Panel D)
Other outcomes:
Locations:
city: Glendale
country: United States
facility: California Clinical Trials ( Site 0001)
state: California
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: