Schizophrenic Disorders
Conditions
Brief summary
This study determined if a single dose of LY2140023 (pomaglumetad methionil) affects the electrical activity in the heart in participants with schizophrenia. This study also helped determine how a single high dose of LY2140023 is tolerated by participants.
Detailed description
The primary objective of this study was to determine that a single supratherapeutic dose of LY2140023 does not differ from placebo in the mean change from baseline in 12-lead electrocardiogram (ECG) QT interval measurements, such that the upper bound of the 2-sided 90% confidence interval (CI) for the greatest time-matched mean effect is \<10 ms in subjects with schizophrenia. The secondary objective was to further evaluate the tolerability of a supratherapeutic single dose of LY2140023 monohydrate. Male or female subjects diagnosed with schizophrenia and aged between 18 and 65 years, inclusive, who had not been hospitalized for psychiatric illness for at least 12 weeks prior to Day 1 of the lead-in period, and who had a Clinical Global Impression - Severity scale score of \<4 were included in the study.
Interventions
DRUGLY2140023
Administered orally.
DRUGPlacebo
Administered orally.
DRUGMoxifloxacin
Administered orally.
Sponsors
Denovo Biopharma LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of schizophrenia * Female participants who are postmenopausal * Not hospitalized for psychiatric illness for at least 12 weeks prior to Day 1 of the study and have a Clinical Global Impression Severity Scale score of \<4 * Willing and able to be hospitalized from Day 1 to the end of the study * Can be washed out of their antipsychotic medication for the duration of the study * Considered reliable, able to understand, and willing to perform all study procedures * Understand the nature of the study and give written informed consent * Clinical laboratory test results within normal reference range * Venous access sufficient to allow blood sampling * Clinically acceptable sitting blood pressure and heart rate
Exclusion criteria
* Currently enrolled in, have completed or have discontinued from a clinical trial involving an investigational drug within the last 30 days * Known allergies to pomaglumetad methionil (LY2140023) or its active metabolite (LY404039), moxifloxacin, related compounds, or components * Previously completed this study or prematurely discontinued from any study after having received at least 1 dose of pomaglumetad methionil (LY2140023) * Received treatment with clozapine * Received aripiprazole within 2 months prior to screening * Taking either thioridazine or thiothixene * Receiving treatment with depot antipsychotic medication within 12 weeks, prior to screening * Taking any medications other than those that are specifically permitted in the protocol * Asthma needing active beta 2 (B2) agonist within 14 days of the study * Active suicidal ideation with some intent to act, without specific plan or with specific plan and intent or had suicidal behavior such as actual attempt, interrupted attempt, aborted attempt, preparatory act, or behavior within the past 3 months * Substance dependence or substance abuse (except nicotine and caffeine) within the 6 months prior to admission * Substance-induced psychosis within 7 days of admission (or at any time during the dosing period) * History of 1 or more seizures (with exceptions) * Screening electroencephalogram (EEG) with paroxysmal (epileptiform) activity * Have had electroconvulsive therapy (ECT) within 3 months of Day 1 of the study or who are expected to have ECT at any time during the live phase of this study * Parkinson's disease, dementia-related psychosis, or related disorders * Untreated hyperthyroidism or hypothyroidism needing a thyroid hormone supplement who have not been on a stable dose of medication for at least 2 months prior to screening * History of leukopenia or agranulocytosis * Alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) or aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) values greater than 2 times the upper limit of normal (ULN) or total bilirubin values greater than 1.5 times the ULN of the performing laboratory at screening * Abnormality in the 12-lead electrocardiogram (ECG) that increases the risks associated with participating in the study * Premature ventricular contraction (PVC) associated with symptoms and/or any complex PVCs * Heart rhythm disturbance by history or ECG at screening * Personal or family history of long QT wave syndrome * Family history of sudden unexplained death or cardiac death in a family member under 60 years of age * Unexplained syncope within the last year * Acute, serious, or unstable medical conditions * Prolactin level of greater than 200 nanograms per milliliter (ng/mL) (200 micrograms per liter \[ug/L\] or 4228 milli-international units per liter \[mIU/L\]) at screening (with the exception of participants treated with risperidone) at screening * Medical history of Human Immunodeficiency Virus positive (HIV+) status * Test positive for (1) Hepatitis C virus antibody or (2) Hepatitis B surface antigen (HBsAg) with or without positive Hepatitis B core total antibody * Smoke greater than or equal to 40 cigarettes per day * Movement disorder that could interfere with conducting 12-lead ECGs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | Baseline, up to 12 hours postdose in each treatment period | The QT interval is a measure of the time between the start of the Q wave and the end of the T wave. QT intervals from quadruplicate electrocardiogram (ECG) data were corrected for heart rate using Fridericia's formula: QTcF = QT/RR\^0.333, where RR is the interval between two R waves. Least squares (LS) mean changes from baseline in QTcF were calculated using a mixed-effects model with baseline QTcF, treatment, time, period, sequence, and the time-by-treatment interaction as fixed effects and participant and the participant-by-period interaction as random effects. |
Countries
United States
Participant flow
Pre-assignment details
All participants had to go through a lead in 7-day antipsychotic medication washout.
Participants by arm
| Arm | Count |
|---|---|
| Overall After completing a 7-day antipsychotic medication washout period (Days 1 to 7), participants still meeting eligibility criteria were randomized to receive single doses of LY2140023 (Treatment A), matching placebo (Treatment B), and moxifloxacin (Treatment C) in 1 of 6 treatment sequences (ABC, BCA, CAB, BAC, CBA, or ACB). Study drug was administered on Days 8, 11, and 14 of the study.
LY2140023 (pomaglumetad methionil): 400 milligrams (mg) (5 x 80 mg tablets), administered orally as a single dose during 1 of 3 treatment periods separated by 2-day washout periods.
placebo: 5 tablets, administered orally as a single dose during 1 of 3 treatment periods separated by 2-day washout periods.
moxifloxacin: 400 mg tablet, administered orally as a single dose during 1 of 3 treatment periods separated by 2-day washout periods. | 86 |
| Total | 86 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Sponsor Decision | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Overall |
|---|---|
| Age, Continuous | 40.3 years STANDARD_DEVIATION 10.5 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 2 participants |
| Race/Ethnicity, Customized Black or African American | 65 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 2 participants |
| Race/Ethnicity, Customized White | 17 participants |
| Region of Enrollment United States | 86 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 84 Participants |
| Weight | 86.73 kilograms STANDARD_DEVIATION 15.76 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 52 / 81 | 13 / 82 | 19 / 80 |
| serious Total, serious adverse events | 1 / 81 | 0 / 82 | 0 / 80 |
Outcome results
Primary
Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc)
The QT interval is a measure of the time between the start of the Q wave and the end of the T wave. QT intervals from quadruplicate electrocardiogram (ECG) data were corrected for heart rate using Fridericia's formula: QTcF = QT/RR\^0.333, where RR is the interval between two R waves. Least squares (LS) mean changes from baseline in QTcF were calculated using a mixed-effects model with baseline QTcF, treatment, time, period, sequence, and the time-by-treatment interaction as fixed effects and participant and the participant-by-period interaction as random effects.
Time frame: Baseline, up to 12 hours postdose in each treatment period
Population: All participants who received at least 1 dose of LY2140023, moxifloxacin, or placebo and had evaluable QTcF data
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| 400 mg LY2140023 | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 12.0 hours | -6.3 milliseconds |
| 400 mg LY2140023 | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 0.5 hours | -7.1 milliseconds |
| 400 mg LY2140023 | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 2.0 hours | -4.7 milliseconds |
| 400 mg LY2140023 | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 3.0 hours | -4.0 milliseconds |
| 400 mg LY2140023 | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 4.0 hours | -1.4 milliseconds |
| 400 mg LY2140023 | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 5.0 hours | -2.0 milliseconds |
| 400 mg LY2140023 | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 6.0 hours | -2.6 milliseconds |
| 400 mg LY2140023 | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 8.0 hours | -5.8 milliseconds |
| 400 mg Moxifloxacin | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 4.0 hours | 3.52 milliseconds |
| 400 mg Moxifloxacin | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 12.0 hours | -3.25 milliseconds |
| 400 mg Moxifloxacin | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 2.0 hours | -2.62 milliseconds |
| 400 mg Moxifloxacin | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 0.5 hours | -6.66 milliseconds |
| 400 mg Moxifloxacin | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 3.0 hours | 0.23 milliseconds |
| Placebo | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 5.0 hours | -3.5 milliseconds |
| Placebo | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 0.5 hours | -7.7 milliseconds |
| Placebo | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 2.0 hours | -7.6 milliseconds |
| Placebo | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 6.0 hours | -6.1 milliseconds |
| Placebo | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 3.0 hours | -6.1 milliseconds |
| Placebo | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 12.0 hours | -8.0 milliseconds |
| Placebo | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 4.0 hours | -2.8 milliseconds |
| Placebo | Change From Baseline up to 12 Hours Postdose in QT Interval Corrected for Heart Rate (QTc) | 8.0 hours | -7.9 milliseconds |
Comparison: Comparison at 0.5 hours postdose.90% CI: [-1.2, 2.44]
Comparison: Comparison at 2.0 hours postdose.90% CI: [1.05, 4.73]
Comparison: Comparison at 3.0 hours postdose.90% CI: [0.28, 3.95]
Comparison: Comparison at 4.0 hours postdose.90% CI: [-0.36, 3.32]
Comparison: Comparison at 5.0 hours postdose.90% CI: [-0.36, 3.32]
Comparison: Comparison at 6.0 hours postdose.90% CI: [1.64, 5.32]
Comparison: Comparison at 8.0 hours postdose.90% CI: [0.27, 3.97]
Comparison: Comparison at 12.0 hours postdose.90% CI: [-0.17, 3.51]
Comparison: Comparison at 0.5 hours postdose.90% CI: [-1.57, 3.59]
Comparison: Comparison at 2.0 hours postdose.90% CI: [2.4, 7.57]
Comparison: Comparison at 3.0 hours postdose.90% CI: [3.71, 8.86]
Comparison: Comparison at 4.0 hours postdose.90% CI: [3.78, 8.93]
Comparison: Comparison at 12.0 hours postdose.90% CI: [2.11, 7.31]