A Study To Evaluate The Effect Of A Supratherapeutic Dose Of Elpipodect (MK-8189) On The QTc Interval In Participants With Schizophrenia (MK-8189-019)

Merck Sharp & Dohme LLC107 enrolled

Overview

The primary purpose of this study to evaluate the effect of a supratherapeutic dose of 80 mg elpipodect on the QT interval corrected for heart rate (QTc interval) and to assess the safety and tolerability of multiple once-daily doses of elpipodect in participants with schizophrenia. The effects of 3 treatment sequences 1) elpipodect (48 mg \[Day 1\] and 80 mg \[Day2\]); 2) standard image placebo (Day 1) and moxifloxacin 400 mg (Day 2); and 3) elpipodect 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 elpipodect dose on Day 2 does not prolong the QTc interval to a clinically significant degree. Specifically, the true mean difference (elpipodect - placebo) in QTc change from baseline is less than 10 milliseconds (msec).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Enrollment

107

Conditions

Schizophrenia

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 Years

Medical Language ↔ Plain English

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). * Had major surgery, donated, or lost 1 unit of blood within 4 weeks prior to the pre-study visit.

Locations (4)

California Clinical Trials Medical Group managed by PAREXEL-PAREXEL International ( Site 0003)

Glendale, California, United States

NRC Research Institute ( Site 0004)

Orange, California, United States

Velocity Clinical Research, Hallandale Beach ( Site 0002)

Hallandale, Florida, United States

Hassman Research Institute Marlton Site ( Site 0001)

Marlton, New Jersey, United States

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)

Number of Participants With Adverse Events (AEs)

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.

Time frame: Up to ~30 days after each dose

Number of Participants Discontinuing Study Therapy Due to AE

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.

Time frame: Up to ~30 days after each dose

Secondary Outcomes

Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment

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.

Time frame: Day 2

Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) of MK-8189

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.

Time frame: 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

Area Under the Plasma Concentration-Time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of MK-8189

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.

Time frame: 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

Cmax is the maximum plasma concentration of MK-8189.

Time frame: 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

C24 is the plasma concentration 24 hours postdose.

Time frame: Day 1 and Day 2: 24 hours postdose

Apparent Terminal Half-life (t½) of MK-8189

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.

Time frame: Day 2: 0.5, 1, 2, 3, 4, 8, 11, 14, 16, 24, 36, 48, 72 hours postdose

Time to Maximum Concentration (Tmax) of MK-8189

Tmax is defined as the time to reach Cmax.

Time frame: 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