A Study To Evaluate The Effect Of A Supratherapeutic Dose Of MK-8189 On The QTc Interval In Participants With Schizophrenia (MK-8189-019)
- Registration Number
- NCT05893862
- Lead Sponsor
- Merck Sharp & Dohme LLC
- Brief Summary
The primary purpose of this study to evaluate the effect of a supratherapeutic dose of 80 mg MK-8189 on the QT interval corrected for heart rate (QTc interval) and to assess the safety and tolerability of multiple once-daily doses of MK-8189 in participants with schizophrenia. The effects of 3 treatment sequences 1) MK-8189 (48 mg \[Day 1\] and 80 mg \[Day2\]); 2) standard image placebo (Day 1) and moxifloxacin 400 mg (Day 2); and 3) MK-8189 placebo (Day 1 and Day 2) were assessed with 5-day washout intervening sequence. Participants received all treatments in a counter-balanced order according to 1 of 6 possible treatment sequences.
The primary hypothesis is that the administration of an 80 mg MK-8189 dose on Day 2 does not prolong the QTc interval to a clinically significant degree. Specifically, the true mean difference (MK-8189 - placebo) in QTc change from baseline is less than 10 milliseconds (msec).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 107
- Meets diagnostic criteria for schizophrenia or schizoaffective disorder according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria.
- Is in the non-acute phase of their illness.
- Has a history of receiving and tolerating antipsychotics medication within the usual dose range employed for schizophrenia.
- Participants with hypothyroidism, diabetes, high blood pressure, chronic respiratory conditions or other medical conditions could be considered if their condition is stable.
- History of a primary DSM-5 axis I psychiatric diagnosis other than schizophrenia or schizoaffective disorder per the allowed DSM-5 criteria.
- History of intellectual disability, borderline personality disorder, anxiety disorder, or organic brain syndrome.
- History of neuroleptic malignant syndrome or moderate to severe tardive dyskinesia (TD).
- History of seizure disorder beyond childhood or is receiving treatment with any anticonvulsant to prevent seizures.
- History of cancer.
- History or presence of sick sinus syndrome, atrioventricular (AV) block, myocardial infarction, pulmonary congestion, cardiac arrhythmia, prolonged QTc interval, or conduction abnormalities.
- History of risk factors for Torsades de Pointes (e.g., heart failure/cardiomyopathy or family history of long QT syndrome).
- History of frequent syncope, vasovagal episodes, or epileptic seizures.
- Family history of sudden cardiac death.
- Has a positive test(s) for hepatitis B surface antigen (HBsAg), hepatitis C antibodies or human immunodeficiency virus (HIV).
- Had major surgery, donated, or lost 1 unit of blood within 4 weeks prior to the pre-study visit.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Sequence 1: MK-8189 (Treatment A)→Moxifloxacin (Treatment B)→Placebo (Treatment C) Moxifloxacin Participants receive a sequence of Treatment A in Period 1 followed by Treatment B in Period 2 followed by Treatment C in Period 3; there will be a 5-day washout between periods. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. Sequence 1: MK-8189 (Treatment A)→Moxifloxacin (Treatment B)→Placebo (Treatment C) Placebo Participants receive a sequence of Treatment A in Period 1 followed by Treatment B in Period 2 followed by Treatment C in Period 3; there will be a 5-day washout between periods. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. Sequence 2: Moxifloxacin (Treatment B) →Placebo (Treatment C) →MK-8189 (Treatment A) MK-8189 Participants receive a sequence of Treatment B in Period 1 followed by Treatment C in Period 2 followed by Treatment A in Period 3; there will be a 5-day washout between periods. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Sequence 2: Moxifloxacin (Treatment B) →Placebo (Treatment C) →MK-8189 (Treatment A) Placebo Participants receive a sequence of Treatment B in Period 1 followed by Treatment C in Period 2 followed by Treatment A in Period 3; there will be a 5-day washout between periods. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Sequence 3: Placebo (Treatment C) →MK-8189 (Treatment A) →Moxifloxacin (Treatment B) MK-8189 Participants receive a sequence of Treatment C in Period 1 followed by Treatment A in in Period 2 followed by Treatment B in Period 3; there will be a 5-day washout between periods. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Sequence 3: Placebo (Treatment C) →MK-8189 (Treatment A) →Moxifloxacin (Treatment B) Placebo Participants receive a sequence of Treatment C in Period 1 followed by Treatment A in in Period 2 followed by Treatment B in Period 3; there will be a 5-day washout between periods. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Sequence 4: Moxifloxacin (Treatment B) → MK-8189 (Treatment A) → Placebo (Treatment C) Placebo Participants receive a sequence of Treatment B in Period 1 followed by Treatment A in Period 2 followed by Treatment C in Period 3; there will be a 5-day washout between periods. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. Sequence 5: MK-8189 (Treatment A) →Placebo (Treatment C) →Moxifloxacin (Treatment B) MK-8189 Participants receive a sequence of Treatment A in Period 1 followed by Treatment C in Period 2 followed by Treatment B in Period 3; there will be a 5-day washout between periods. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Sequence 5: MK-8189 (Treatment A) →Placebo (Treatment C) →Moxifloxacin (Treatment B) Moxifloxacin Participants receive a sequence of Treatment A in Period 1 followed by Treatment C in Period 2 followed by Treatment B in Period 3; there will be a 5-day washout between periods. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Sequence 5: MK-8189 (Treatment A) →Placebo (Treatment C) →Moxifloxacin (Treatment B) Placebo Participants receive a sequence of Treatment A in Period 1 followed by Treatment C in Period 2 followed by Treatment B in Period 3; there will be a 5-day washout between periods. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Sequence 6: Placebo (Treatment C) →Moxifloxacin (Treatment B) → MK-8189 (Treatment A) MK-8189 Participants receive a sequence of Treatment C in Period 1 followed by Treatment B in Period 2 followed by Treatment A in Period 3; there will be a 5-day washout between periods. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Sequence 6: Placebo (Treatment C) →Moxifloxacin (Treatment B) → MK-8189 (Treatment A) Moxifloxacin Participants receive a sequence of Treatment C in Period 1 followed by Treatment B in Period 2 followed by Treatment A in Period 3; there will be a 5-day washout between periods. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Sequence 6: Placebo (Treatment C) →Moxifloxacin (Treatment B) → MK-8189 (Treatment A) Placebo Participants receive a sequence of Treatment C in Period 1 followed by Treatment B in Period 2 followed by Treatment A in Period 3; there will be a 5-day washout between periods. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Sequence 1: MK-8189 (Treatment A)→Moxifloxacin (Treatment B)→Placebo (Treatment C) MK-8189 Participants receive a sequence of Treatment A in Period 1 followed by Treatment B in Period 2 followed by Treatment C in Period 3; there will be a 5-day washout between periods. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. Sequence 4: Moxifloxacin (Treatment B) → MK-8189 (Treatment A) → Placebo (Treatment C) MK-8189 Participants receive a sequence of Treatment B in Period 1 followed by Treatment A in Period 2 followed by Treatment C in Period 3; there will be a 5-day washout between periods. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. Sequence 2: Moxifloxacin (Treatment B) →Placebo (Treatment C) →MK-8189 (Treatment A) Moxifloxacin Participants receive a sequence of Treatment B in Period 1 followed by Treatment C in Period 2 followed by Treatment A in Period 3; there will be a 5-day washout between periods. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Sequence 3: Placebo (Treatment C) →MK-8189 (Treatment A) →Moxifloxacin (Treatment B) Moxifloxacin Participants receive a sequence of Treatment C in Period 1 followed by Treatment A in in Period 2 followed by Treatment B in Period 3; there will be a 5-day washout between periods. Treatment C consists of placebo administered orally on Day 1 and Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Sequence 4: Moxifloxacin (Treatment B) → MK-8189 (Treatment A) → Placebo (Treatment C) Moxifloxacin Participants receive a sequence of Treatment B in Period 1 followed by Treatment A in Period 2 followed by Treatment C in Period 3; there will be a 5-day washout between periods. Treatment B consists of placebo administered orally on Day 1 and moxifloxacin administered orally at 400 mg on Day 2. Treatment A consists of MK-8189 administered orally at 48 mg on Day 1 and 80 mg on Day 2. Treatment C consists of placebo administered orally on Day 1 and Day 2.
- Primary Outcome Measures
Name Time Method Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment Day 1 (MK-8189 48 mg and placebo) and Day 2 (MK-8189 80 mg and placebo) Electrocardiogram data was obtained using a digital Holter device and the Fridericia correction of the QT interval (QTcF) was determined. The change from baseline in QTcF (ΔQTcF \[msec\]) was calculated by subtracting the QTcF value at the timepoint from the QTcF baseline value. Negative values represent a decrease from baseline and vice versa. An average of up to 9 predose ECGs on Day 1 served as baseline to compare postdose effects. Per protocol, the primary endpoint compares MK-8189 to placebo.
Number of Participants With Adverse Events (AEs) Up to ~30 days after each dose An AE is 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.
Number of Participants Discontinuing Study Therapy Due to AE Up to ~30 days after each dose An AE is 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.
- Secondary Outcome Measures
Name Time Method Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) of MK-8189 Day 1: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 14, 24 hours postdose; Day 2: 0.5, 1, 2, 3, 4, 8, 11, 14, 16, 24 hours postdose AUC0-24 is defined as the area under concentration-time curve from 0 to 24 hours postdose. Blood samples taken at pre-dose and up to 24 hours post-dose will be used to determine the AUC0-24 of MK-8189.
Apparent Terminal Half-life (t½) of MK-8189 Day 2: 0.5, 1, 2, 3, 4, 8, 11, 14, 16, 24, 36, 48, 72 hours postdose t½ is the time required for the Cmax plasma concentration to reduce by 50%. Per protocol, t½ was determined only for MK-8189 80 mg.
Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment Day 2 Electrocardiogram data was obtained using a digital Holter device and the Fridericia correction of the QT interval (QTcF) was determined. The change from baseline in QTcF (ΔQTcF \[msec\]) was calculated by subtracting the QTcF value at the timepoint from the QTcF baseline value. Negative values represent a decrease from baseline and vice versa. An average of up to 9 predose ECGs on Day 1 served as baseline to compare postdose effects. Per protocol, the secondary endpoint compares moxifloxacin to placebo on Day 2. Moxifloxacin was tested for statistical significance 1 to 4 hours postdose (ie, around moxifloxacin Cmax) to ensure assay sensitivity. Hochberg's step-up method was applied to preserve the overall α level at .05 for the hypothesis testing.
Area Under the Plasma Concentration-Time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of MK-8189 Day 1: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 14, 24 hours postdose; Day 2: 0.5, 1, 2, 3, 4, 8, 11, 14, 16, 24, 36, 48, and 72 hours postdose AUC0-last is defined as the area under concentration-time curve from 0 to 24 hours. Blood samples taken at pre-dose and up to 72 hours post-dose will be used to extrapolate the AUC0-last of MK-8189.
Maximum Concentration (Cmax) of MK-8189 Day 1: predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 14, 24 hours postdose; Day 2: 0.5, 1, 2, 3, 4, 8, 11, 14, 16, 24, 36, 48, 72 hours postdose Cmax is the maximum plasma concentration of MK-8189.
Concentration of MK-8189 at 24 Hours (C24) Post-dose Day 1 and Day 2: 24 hours postdose C24 is the plasma concentration 24 hours postdose.
Time to Maximum Concentration (Tmax) of MK-8189 Day 1: Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 12, 14, and 24 hours postdose; Day 2: 0.5, 1, 2, 3, 4, 8, 11, 14, 16, 24, 36, 48, and 72 hours postdose Tmax is defined as the time to reach Cmax.
Trial Locations
- Locations (4)
California Clinical Trials Medical Group managed by PAREXEL-PAREXEL International ( Site 0003)
🇺🇸Glendale, California, United States
Hassman Research Institute Marlton Site ( Site 0001)
🇺🇸Marlton, New Jersey, United States
NRC Research Institute ( Site 0004)
🇺🇸Orange, California, United States
Velocity Clinical Research, Hallandale Beach ( Site 0002)
🇺🇸Hallandale Beach, Florida, United States