A Double-Blind, Cross-Over Placebo-Controlled and Active-Controlled Trial To Evaluate The Effect Of A Supratherapeutic Dose Of MK-8189 On The QTc Interval In Participants With Schizophrenia
Overview
- Phase
- Phase 1
- Intervention
- MK-8189
- Conditions
- Schizophrenia
- Sponsor
- Merck Sharp & Dohme LLC
- Enrollment
- 107
- Locations
- 4
- Primary Endpoint
- Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment
- Status
- Completed
- Last Updated
- last year
Overview
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).
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
Exclusion Criteria
- •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).
Arms & Interventions
Sequence 1: MK-8189 (Treatment A)→Moxifloxacin (Treatment B)→Placebo (Treatment C)
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.
Intervention: MK-8189
Sequence 1: MK-8189 (Treatment A)→Moxifloxacin (Treatment B)→Placebo (Treatment C)
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.
Intervention: Moxifloxacin
Sequence 1: MK-8189 (Treatment A)→Moxifloxacin (Treatment B)→Placebo (Treatment C)
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.
Intervention: Placebo
Sequence 2: Moxifloxacin (Treatment B) →Placebo (Treatment C) →MK-8189 (Treatment A)
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.
Intervention: MK-8189
Sequence 2: Moxifloxacin (Treatment B) →Placebo (Treatment C) →MK-8189 (Treatment A)
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.
Intervention: Moxifloxacin
Sequence 2: Moxifloxacin (Treatment B) →Placebo (Treatment C) →MK-8189 (Treatment A)
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.
Intervention: Placebo
Sequence 3: Placebo (Treatment C) →MK-8189 (Treatment A) →Moxifloxacin (Treatment B)
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.
Intervention: MK-8189
Sequence 3: Placebo (Treatment C) →MK-8189 (Treatment A) →Moxifloxacin (Treatment B)
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.
Intervention: Moxifloxacin
Sequence 3: Placebo (Treatment C) →MK-8189 (Treatment A) →Moxifloxacin (Treatment B)
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.
Intervention: Placebo
Sequence 4: Moxifloxacin (Treatment B) → MK-8189 (Treatment A) → Placebo (Treatment C)
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.
Intervention: MK-8189
Sequence 4: Moxifloxacin (Treatment B) → MK-8189 (Treatment A) → Placebo (Treatment C)
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.
Intervention: Moxifloxacin
Sequence 4: Moxifloxacin (Treatment B) → MK-8189 (Treatment A) → Placebo (Treatment C)
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.
Intervention: Placebo
Sequence 5: MK-8189 (Treatment A) →Placebo (Treatment C) →Moxifloxacin (Treatment B)
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.
Intervention: MK-8189
Sequence 5: MK-8189 (Treatment A) →Placebo (Treatment C) →Moxifloxacin (Treatment B)
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.
Intervention: Moxifloxacin
Sequence 5: MK-8189 (Treatment A) →Placebo (Treatment C) →Moxifloxacin (Treatment B)
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.
Intervention: Placebo
Sequence 6: Placebo (Treatment C) →Moxifloxacin (Treatment B) → MK-8189 (Treatment A)
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.
Intervention: MK-8189
Sequence 6: Placebo (Treatment C) →Moxifloxacin (Treatment B) → MK-8189 (Treatment A)
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.
Intervention: Moxifloxacin
Sequence 6: Placebo (Treatment C) →Moxifloxacin (Treatment B) → MK-8189 (Treatment A)
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.
Intervention: Placebo
Outcomes
Primary Outcomes
Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment
Time Frame: 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)
Time Frame: 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
Time Frame: 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 Outcomes
- 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)
- 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)
- Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment(Day 2)
- 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)
- 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)
- Concentration of MK-8189 at 24 Hours (C24) Post-dose(Day 1 and Day 2: 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)