Clinical trial NCT04506905: Safety, Tolerability, and Pharmacokinetics Study of MK-8189 in Participants With Schizophrenia and Healthy Participants (MK-8189-011)
Official title: A 2-Part Randomized Clinical Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Alternate MK-8189 Titration Regimens in Young Adult Participants With Schizophrenia and to Evaluate the Safety, Tolerability and Pharmacokinetics of MK-8189 in Elderly Participants With Schizophrenia and Healthy Elderly
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Schizophrenia
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2020-08-10
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized, double-blind, 2-part clinical study of the safety, tolerability and pharmacokinetics of alternate MK-8189 titration regimens. Part 1 assessed multiple dose once-daily titration regimens of MK-8189 in young adult participants with schizophrenia. Part 2 assessed multiple once-daily doses of MK-8189 in elderly participants with schizophrenia and healthy elderly participants.


Eligibility criteria: Inclusion Criteria:

* Has a body mass index (BMI) ≤40 kg/m2
* Has no clinically significant abnormality on 12-lead safety electrocardiogram (ECG) performed at the prestudy (screening) visit and/or prior to randomization
* Has a normal resting blood pressure (BP: systolic BP is ≥90 millimeter of mercury \[mmHg\] and ≤140 mmHg; diastolic BP is ≥60 mmHg and ≤90 mmHg) and normal resting heart rate (≥45 beats per minute \[bpm\] and ≤100 bpm) in the semirecumbent position at the prestudy (screening) visit and/or prior to randomization. Repeat evaluations may be done if the values for a participant are, per investigator discretion, minimally outside the designated range. Participants may be included if values are outside the normal range but considered not clinically significant per investigator discretion
* Participants with schizophrenia only: Meets diagnostic criteria for schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (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
* Participants with schizophrenia only: Has a total Brief Psychiatric Rating Scale (BPRS) score of \<48 with a BPRS score \<4 for #10 (hostility) and #14 (uncooperativeness) at the screening visit
* Participants with schizophrenia only: Is in the nonacute phase of their illness and clinically stable for 3 months prior to screening as demonstrated by the following: 1) 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 2) no increase in level of psychiatric care due to worsening of symptoms of schizophrenia for 3 months prior to screening
* Participants with schizophrenia only: Has a history of receiving and tolerating antipsychotic medication within the usual dose range employed for schizophrenia
* Participants with schizophrenia only: Has a stable living situation
* Participants with hypothyroidism, diabetes, high BP, chronic respiratory conditions or other mild forms of these medical conditions could be considered as candidates for study enrollment if their condition is stable
* Has regular bowel movements
* Participants with schizophrenia only: 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
* Female participants are not pregnant and not breastfeeding, and are not a woman of childbearing potential (WOCBP) or are a WOCBP who agrees to follow contraceptive guidance during the treatment period and for at least 14 days after the last dose of study intervention

Exclusion Criteria:

* Is a WOCBP who has a positive urine pregnancy test within 48 hours before the first dose of study intervention
* Participants with schizophrenia only: 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 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
* Has a substance-induced psychotic disorder or behavioral disturbance thought to be due to substance abuse
* Has a DSM-5 defined substance use disorder within 3 months of screening
* Has a history of seizure disorder beyond childhood or is receiving treatment with any anticonvulsant to prevent seizures
* Has an untreated or uncompensated clinically significant renal, endocrine, hepatic, respiratory, gastrointestinal, psychiatric, neurologic, cardiovascular, hematological, immunological or cerebrovascular disease, malignancy, allergic disease or other chronic and/or degenerative process at screening
* Has any clinically significant abnormal laboratory, vital sign (VS), physical examination, or 12-lead safety ECG findings at screening or changes from baseline parameters or, in the opinion of the investigator, would make the participant inappropriate for entry into this study
* Has a history of cancer with following exceptions: 1) Adequately treated nonmelanomatous skin carcinoma or carcinoma in situ of the cervix or; 2) Other malignancies which have been successfully treated with appropriate follow up and therefore unlikely to recur for the duration of the study, in the opinion of the investigator and with agreement of the Sponsor
* Has a clinically significant history or presence of sick sinus syndrome, first, second, or third-degree AV block, myocardial infarction, pulmonary congestion, cardiac arrhythmia, prolonged corrected QT (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
* For Part 2 participants only: Participant has an estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73 m2 based on the modification of diet in renal disease (MDRD). Participants who have an eGFR or measured creatinine clearance of up to10% below of either 60 milliliter/minute \[mL/min\] (for creatinine clearance) or 60 mL/min/1.73m2 (for eGFR) may be enrolled in the study at the discretion of the investigator
* Has a history of significant multiple and/or severe allergies or has had an anaphylactic reaction or significant intolerability to prescription or non-prescription drugs or food
* Is positive for Hepatitis B surface antigen, Hepatitis C antibodies or HIV
* Had major surgery, donated or lost 1 unit of blood within 4 weeks prior to the prestudy (screening) visit
* Healthy participants only: Is mentally or legally incapacitated, has significant emotional problems at the time of prestudy (screening) visit or expected during the conduct of the study or 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 investigator's discretion)
* Participants with schizophrenia only: 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
* Healthy participants only: Is at imminent risk of self-harm, based on clinical interview and responses on the CSSRS, 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 in the past 5 years or suicidal behavior in their lifetime
* Has received treatment with clozapine for schizophrenia or treatment with monoamine oxidase inhibitors within 3 months of screening or cariprazine within 2 months of screening
* Has received a parenteral depot antipsychotic medication within 3 months of screening
* Is unable to refrain from the use of co-medication with a moderate or strong inhibiting or inducing effect on cytochrome (CYP3A) and/or cytochrome (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 cytochrome (CYP2B6)
* Has participated in another investigational study within 4 weeks (or 5 half-lives, whichever is greater) prior to the prestudy (screening) visit
* Has been in incarceration or imprisonment within three months prior to screening
* Is a current smoker (healthy participants only) or is a smoker (participants with schizophrenia only) that does not agree to follow the smoking restrictions as defined by the clinical research unit (CRU)
* 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 of caffeinated beverages per day
* Is a regular user of cannabis, any illicit drugs or has a history of drug abuse within approximately 3 years
* Presents any concern by the investigator regarding safe participation in the study or for any other reason the investigator considers the participant inappropriate for participation in the study
* Is or has an immediate family member who is investigational site or Sponsor staff directly involved with this study

Primary outcomes:
measure: Part 1 & 2: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 27 days
measure: Part 1 & 2: Number of Participants Discontinuing Study Treatment Due to an AE
timeFrame: Up to approximately 27 days
Secondary outcomes:
measure: Part 1: Area Under the Concentration Time-curve From Hour 0 to 24 Hours Postdose (AUC0-24) of MK-8189
timeFrame: Days 1, 2, 4, and Day 7: Predose and 2, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part 1: Concentration 24 Hours Postdose (C24) of MK-8189
timeFrame: Days 1, 2, 4, and Day 7: Predose and 2, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part 1: Maximum Plasma Concentration (Cmax) of MK-8189
timeFrame: Days 1, 2, 3, 4, and Day 7: Predose and 2, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part 1: Time to Maximum Concentration (Tmax) of MK-8189
timeFrame: Days 1, 2, 3, 4, and Day 7: Predose and 2, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part 1: Clearance (CL/F) of MK-8189
timeFrame: Day 7: Predose and 2, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part 1: Apparent Terminal Half-life (t½) of MK-8189
timeFrame: Day 7: Predose and 2, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part 1: Volume of Distribution (Vd/F) of MK-8189
timeFrame: Day 7: Predose and 2, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part 2: AUC0-24 of MK-8189
timeFrame: Days 1, 4, 7, 10, and 13: Predose and 2, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part 2: C24 of MK-8189
timeFrame: Days 1, 4, 7, 10, and 13: Predose and 2, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part 2: Cmax of MK-8189
timeFrame: Days 1, 4, 7, 10, and 13: Predose and 2, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part 2: Tmax of MK-8189
timeFrame: Days 1, 4, 7, 10, and 13: Predose and 2, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part 2: CL/F of MK-8189
timeFrame: Days 10 and 13: Predose and 2, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part 2: t½ of MK-8189
timeFrame: Days 10 and 13: Predose and 2, 6, 8, 10, 12, 16, and 24 hours postdose
measure: Part 2: Vd/F of MK-8189
timeFrame: Days 10 and 13: Predose and 2, 6, 8, 10, 12, 16, and 24 hours postdose
Other outcomes:
Locations:
city: Rogers
country: United States
facility: Woodland Research Northwest, LLC ( Site 0002)
state: Arkansas
city: Glendale
country: United States
facility: Parexel ( Site 0004)
state: California
city: Long Beach
country: United States
facility: Collaborative NeuroScience Network ( Site 0008)
state: California
city: Hallandale Beach
country: United States
facility: Velocity Clinical Research, Hallandale Beach ( Site 0001)
state: Florida
city: Oakland Park
country: United States
facility: RCA at Fort Lauderdale Behavioral Health Center ( Site 0006)
state: Florida
city: Berlin
country: United States
facility: Hassman Research Institute ( Site 0007)
state: New Jersey
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: