Schizophrenia
Conditions
Brief summary
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).
Interventions
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Contacts
STUDY_DIRECTORMedical Director
Merck Sharp & Dohme LLC
Participant flow
Recruitment details
Participants with stable schizophrenia or schizoaffective disorder were enrolled at 4 study sites in the US.
Pre-assignment details
Treatments were administered in a counterbalanced manner on Day 1 and Day 2 of each of 3 treatment periods. Periods 1 and 2 were separated by 5-day washout. 'A' refers to MK-8189 48 mg (Day 1) and 80 mg (Day 2); 'B' refers to Standard Image Placebo (Day 1) and Moxifloxacin 400 mg (Day 2); and 'C' refers to placebo to MK-8189 (Days 1 and 2).
Participants by arm
| Arm | Count |
|---|---|
| Sequence A/B/C Participants received treatment sequence A/B/C. | 15 |
| Sequence ACB Participants received treatment sequence A/C/B. | 25 |
| Sequence B/A/C Participants received treatment sequence B/A/C. | 15 |
| Sequence B/C/A Participants received treatment sequence B/C/A. | 18 |
| Sequence C/A/B Participants received treatment sequence C/A/B. | 20 |
| Sequence C/B/A Participants received treatment sequence C/B/A. | 14 |
| Total | 107 |
Baseline characteristics
| Characteristic | Sequence A/B/C | Sequence ACB | Sequence B/A/C | Sequence B/C/A | Sequence C/A/B | Sequence C/B/A | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 45.5 years STANDARD_DEVIATION 12.3 | 46.0 years STANDARD_DEVIATION 10.9 | 43.5 years STANDARD_DEVIATION 9.8 | 46.8 years STANDARD_DEVIATION 7.6 | 44.1 years STANDARD_DEVIATION 9.3 | 45.9 years STANDARD_DEVIATION 11.2 | 45.4 years STANDARD_DEVIATION 10 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 1 Participants | 4 Participants | 2 Participants | 3 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 23 Participants | 14 Participants | 14 Participants | 18 Participants | 11 Participants | 94 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 21 Participants | 13 Participants | 14 Participants | 17 Participants | 9 Participants | 86 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 3 Participants | 2 Participants | 2 Participants | 1 Participants | 5 Participants | 16 Participants |
| Sex: Female, Male Female | 3 Participants | 8 Participants | 3 Participants | 4 Participants | 3 Participants | 3 Participants | 24 Participants |
| Sex: Female, Male Male | 12 Participants | 17 Participants | 12 Participants | 14 Participants | 17 Participants | 11 Participants | 83 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 98 | 0 / 92 | 0 / 90 | 0 / 89 | 0 / 89 |
| other Total, other adverse events | 24 / 98 | 21 / 92 | 15 / 90 | 7 / 89 | 11 / 89 |
| serious Total, serious adverse events | 1 / 98 | 0 / 92 | 1 / 90 | 0 / 89 | 0 / 89 |
Outcome results
Primary
Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 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 primary endpoint compares MK-8189 to placebo.
Time frame: Day 1 (MK-8189 48 mg and placebo) and Day 2 (MK-8189 80 mg and placebo)
Population: All participants who received ≥1 dose of MK-8189, and who complied with the protocol sufficiently to ensure that generated data will likely exhibit the effects of treatment (according to the underlying scientific model), are included.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| MK-8189 48 mg Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 2 hr | 2.68 ΔQTcF (msec) |
| MK-8189 48 mg Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 8 hr | 8.75 ΔQTcF (msec) |
| MK-8189 48 mg Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 24 hr | 4.31 ΔQTcF (msec) |
| MK-8189 48 mg Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 12 hr (Day 1) or 11 hr (Day 2) | 4.26 ΔQTcF (msec) |
| MK-8189 48 mg Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 14 hr | 8.10 ΔQTcF (msec) |
| MK-8189 48 mg Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 0.5 Hr | -0.61 ΔQTcF (msec) |
| MK-8189 48 mg Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 1 hr | 0.29 ΔQTcF (msec) |
| MK-8189 48 mg Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 6 hr (Day 1 only) | 7.38 ΔQTcF (msec) |
| MK-8189 48 mg Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 4 hr | 2.80 ΔQTcF (msec) |
| MK-8189 48 mg Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 3 hr | 2.18 ΔQTcF (msec) |
| Placebo Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 8 hr | -0.97 ΔQTcF (msec) |
| Placebo Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 1 hr | 0.48 ΔQTcF (msec) |
| Placebo Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 2 hr | 1.06 ΔQTcF (msec) |
| Placebo Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 3 hr | -1.35 ΔQTcF (msec) |
| Placebo Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 12 hr (Day 1) or 11 hr (Day 2) | 0.33 ΔQTcF (msec) |
| Placebo Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 0.5 Hr | -1.13 ΔQTcF (msec) |
| Placebo Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 4 hr | -3.19 ΔQTcF (msec) |
| Placebo Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 6 hr (Day 1 only) | 0.25 ΔQTcF (msec) |
| Placebo Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 14 hr | 4.09 ΔQTcF (msec) |
| Placebo Day 1 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 24 hr | -1.38 ΔQTcF (msec) |
| MK-8189 80 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 8 hr | 2.82 ΔQTcF (msec) |
| MK-8189 80 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 12 hr (Day 1) or 11 hr (Day 2) | 3.84 ΔQTcF (msec) |
| MK-8189 80 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 4 hr | 2.64 ΔQTcF (msec) |
| MK-8189 80 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 2 hr | 5.14 ΔQTcF (msec) |
| MK-8189 80 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 24 hr | 0.24 ΔQTcF (msec) |
| MK-8189 80 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 3 hr | 3.31 ΔQTcF (msec) |
| MK-8189 80 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 16 hr (Day 2 only) | 10.47 ΔQTcF (msec) |
| MK-8189 80 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 1 hr | 3.60 ΔQTcF (msec) |
| MK-8189 80 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | Predose (Day 2 only) | 4.31 ΔQTcF (msec) |
| MK-8189 80 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 14 hr | 7.84 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 24 hr | -1.61 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | Predose (Day 2 only) | -1.38 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 1 hr | -0.76 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 6 hr (Day 1 only) | -3.10 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 4 hr | -2.67 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 3 hr | -2.22 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 14 hr | 5.20 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 2 hr | 0.92 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 12 hr (Day 1) or 11 hr (Day 2) | 0.84 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 16 hr (Day 2 only) | 5.20 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following MK-8189 Treatment | 8 hr | -1.93 ΔQTcF (msec) |
90% CI: [-1.11, 2.14]
90% CI: [-1.26, 1.98]
90% CI: [-1.04, 3.66]
90% CI: [1.9, 6.64]
90% CI: [4.35, 9.64]
90% CI: [4.35, 9.64]
90% CI: [6.71, 11.8]
90% CI: [2.27, 7.35]
90% CI: [0.91, 6.23]
90% CI: [3.18, 6.85]
90% CI: [1.56, 6.34]
90% CI: [1.49, 6.35]
90% CI: [2.33, 7.03]
90% CI: [2.45, 7.12]
90% CI: [1.93, 7.71]
90% CI: [2.51, 8.09]
90% CI: [2.97, 8.74]
90% CI: [1.79, 6.45]
90% CI: [-1.69, 3.26]
Primary
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
Population: All treated participants are included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-8189 48 mg Day 1 | Number of Participants Discontinuing Study Therapy Due to AE | 3 Participants |
| Placebo Day 1 | Number of Participants Discontinuing Study Therapy Due to AE | 1 Participants |
| MK-8189 80 mg Day 2 | Number of Participants Discontinuing Study Therapy Due to AE | 4 Participants |
| Placebo Day 2 | Number of Participants Discontinuing Study Therapy Due to AE | 0 Participants |
| Standard Image Placebo Day 1 | Number of Participants Discontinuing Study Therapy Due to AE | 2 Participants |
Primary
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
Population: All treated participants are included.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MK-8189 48 mg Day 1 | Number of Participants With Adverse Events (AEs) | 25 Participants |
| Placebo Day 1 | Number of Participants With Adverse Events (AEs) | 16 Participants |
| MK-8189 80 mg Day 2 | Number of Participants With Adverse Events (AEs) | 21 Participants |
| Placebo Day 2 | Number of Participants With Adverse Events (AEs) | 7 Participants |
| Standard Image Placebo Day 1 | Number of Participants With Adverse Events (AEs) | 11 Participants |
Secondary
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
Population: All participants who received MK-8189 80 mg, had sufficient terminal phase data, and who complied with the protocol sufficiently to ensure that generated data will likely exhibit the effects of treatment (according to the underlying scientific model), are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Day 1 | Apparent Terminal Half-life (t½) of MK-8189 | 9.89 hours | Geometric Coefficient of Variation 29.2 |
Secondary
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
Population: All participants who received ≥1 dose of MK-8189, and who complied with the protocol sufficiently to ensure that generated data will likely exhibit the effects of treatment (according to the underlying scientific model), are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8189 48 mg Day 1 | Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) of MK-8189 | 18500 hr*nM | Geometric Coefficient of Variation 50.2 |
| MK-8189 80 mg Day 2 | Area Under the Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC0-24) of MK-8189 | 41200 hr*nM | Geometric Coefficient of Variation 54 |
Secondary
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
Population: All participants who received ≥1 dose of MK-8189, and who complied with the protocol sufficiently to ensure that generated data will likely exhibit the effects of treatment (according to the underlying scientific model), are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8189 48 mg Day 1 | Area Under the Plasma Concentration-Time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of MK-8189 | 17400 hr*nM | Geometric Coefficient of Variation 61.6 |
| MK-8189 80 mg Day 2 | Area Under the Plasma Concentration-Time Curve From Time 0 to Last Measurable Concentration (AUC0-last) of MK-8189 | 54100 hr*nM | Geometric Coefficient of Variation 95.9 |
Secondary
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
Population: All participants who received ≥1 dose of moxifloxacin, and who complied with the protocol sufficiently to ensure that generated data will likely exhibit the effects of treatment (according to the underlying scientific model), are included.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 3 hr | -2.22 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 4 hr | -2.67 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 11 hr | -1.93 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | Predose (Day 2 only) | -1.38 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 0.5 hr (Day 1 only) | -1.38 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 1 hr | -0.76 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 2 hr | 0.92 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 8 hr | -3.10 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 14 hr | 0.84 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 16 hr | 5.20 ΔQTcF (msec) |
| Placebo Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 24 hr | -.61 ΔQTcF (msec) |
| Moxifloxacin 400 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 3 hr | 8.92 ΔQTcF (msec) |
| Moxifloxacin 400 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 2 hr | 11.03 ΔQTcF (msec) |
| Moxifloxacin 400 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 4 hr | 4.70 ΔQTcF (msec) |
| Moxifloxacin 400 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 14 hr | 10.12 ΔQTcF (msec) |
| Moxifloxacin 400 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 24 hr | 2.33 ΔQTcF (msec) |
| Moxifloxacin 400 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | Predose (Day 2 only) | 0.92 ΔQTcF (msec) |
| Moxifloxacin 400 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 8 hr | 3.50 ΔQTcF (msec) |
| Moxifloxacin 400 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 11 hr | 5.45 ΔQTcF (msec) |
| Moxifloxacin 400 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 1 hr | 9.77 ΔQTcF (msec) |
| Moxifloxacin 400 mg Day 2 | Change From Baseline in QT Interval Corrected for Heart Rate (QTc) Following Moxifloxacin Treatment | 16 hr | 12.48 ΔQTcF (msec) |
p-value: <0.000190% CI: [7.4, 11.04]t-test, 1 sided
p-value: 0.014190% CI: [6.31, 10.56]t-test, 1 sided
p-value: <0.000190% CI: [8.85, 12.74]t-test, 1 sided
p-value: 0.104590% CI: [3.96, 8.91]t-test, 1 sided
90% CI: [4.66, 8.38]
90% CI: [4.74, 9.93]
90% CI: [3.95, 8.88]
90% CI: [0.81, 4.76]
Secondary
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
Population: All participants who received ≥1 dose of MK-8189, and who complied with the protocol sufficiently to ensure that generated data will likely exhibit the effects of treatment (according to the underlying scientific model), are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8189 48 mg Day 1 | Concentration of MK-8189 at 24 Hours (C24) Post-dose | 992 nM | Geometric Coefficient of Variation 83.7 |
| MK-8189 80 mg Day 2 | Concentration of MK-8189 at 24 Hours (C24) Post-dose | 1660 nM | Geometric Coefficient of Variation 87.4 |
Secondary
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
Population: All participants who received ≥1 dose of MK-8189, and who complied with the protocol sufficiently to ensure that generated data will likely exhibit the effects of treatment (according to the underlying scientific model), are included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| MK-8189 48 mg Day 1 | Maximum Concentration (Cmax) of MK-8189 | 1290 nM | Geometric Coefficient of Variation 50.6 |
| MK-8189 80 mg Day 2 | Maximum Concentration (Cmax) of MK-8189 | 2360 nM | Geometric Coefficient of Variation 52.4 |
Secondary
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
Population: All participants who received ≥1 dose of MK-8189, and who complied with the protocol sufficiently to ensure that generated data will likely exhibit the effects of treatment (according to the underlying scientific model), are included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MK-8189 48 mg Day 1 | Time to Maximum Concentration (Tmax) of MK-8189 | 14.08 hours |
| Placebo Day 1 | Time to Maximum Concentration (Tmax) of MK-8189 | 14.13 hours |