Long QT Syndrome
Conditions
Keywords
Hepatic Impairment
Brief summary
The primary objective of this study is to evaluate the pharmacokinetic (PK) profile of oral eleclazine and its metabolite, GS-623134, in participants with normal and impaired hepatic function. Participants in the healthy control group will be matched to participants with impaired hepatic function by age (± 5 years), gender, and body mass index (± 10%).
Interventions
DRUGEleclazine
Eleclazine tablets administered orally
Sponsors
Gilead Sciences
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
All participants: * Be a nonsmoker or consume \< 20 cigarettes per day * Have a calculated body mass index (BMI) from 18 to 36 kg/m\^2, inclusive, at study screening * Have a creatinine clearance (CrCl) ≥ 60 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at screening * Have either a normal 12-lead electrocardiogram (ECG) or one with abnormalities that are considered clinically insignificant by the investigator * Screening labs within defined thresholds Participants with mild, moderate, or severe hepatic impairment must also meet the following additional inclusion criteria: * Must have diagnosis of chronic (\> 6 months), stable hepatic impairment with no clinically significant changes within 3 months (90 days) prior to study drug administration (Day 1) * Individuals with severe hepatic impairment must have a score on the Child-Pugh-Turcotte scale of 10-15 at screening. If an individual's score changes during the course of the study, the score at screening will be used for classification. * Individuals with moderate hepatic impairment must have a score on the Child-Pugh-Turcotte scale of 7-9 at screening. If an individual's score changes during the course of the study, the score at Screening will be used for classification. * Individuals with mild hepatic impairment must have a score on the Child-Pugh-Turcotte scale of 5-6 at screening. If an individual's score changes during the course of the study, the score at screening will be used for classification.
Exclusion criteria
* Pregnant or lactating females * History of meningitis or encephalitis, epilepsy, seizures, migraines, tremors, myoclonic jerks, narcolepsy, obstructive sleep apnea, anxiety, syncope, head injuries or a family history of seizures * Presence or history of cardiovascular disease (including history of myocardial infarction based on ECG and/or clinical history, any history of ventricular tachycardia, congestive heart failure, cardiomyopathy, or left ventricular ejection fraction \< 40%), cardiac conduction abnormalities, a family history of Long QT Syndrome, or unexplained death in an otherwise healthy individual between the ages of 1 and 30 years * Syncope, palpitations, or unexplained dizziness * Implanted defibrillator or pacemaker * Are unable to comply with study requirements or are otherwise believed, by the study investigator, to be inappropriate for study participation for any reason Participants with mild, moderate, or severe hepatic impairment must also meet the following additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK (Pharmacokinetic) Parameter: AUCinf of Eleclazine | Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48, 72, 96, 120 hours on Day 1 and approximately the same time in the morning as predose of Day 1 on Days 15, 29, 43, and 57 | AUCinf was defined as the concentration of drug extrapolated to infinite time (area under the plasma concentration versus time curve extrapolated to infinite time). |
| PK Parameter: AUCinf of GS-623134 (Metabolite of Eleclazine) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48, 72, 96, 120 hours on Day 1 and approximately the same time in the morning as predose of Day 1 on Days 15, 29, 43, and 57 | AUCinf was defined as the concentration of drug extrapolated to infinite time (area under the plasma concentration versus time curve extrapolated to infinite time). |
| PK Parameter: Cmax of Eleclazine | Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48, 72, 96, 120 hours on Day 1 and approximately the same time in the morning as predose of Day 1 on Days 15, 29, 43, and 57 | Cmax was defined as the maximum observed concentration of drug in plasma. |
| PK Parameter: Cmax of GS-623134 (Metabolite of Eleclazine) | Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48, 72, 96, 120 hours on Day 1 and approximately the same time in the morning as predose of Day 1 on Days 15, 29, 43, and 57 | Cmax was defined as the maximum observed concentration of drug in plasma. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Treatment-Emergent Adverse Events | First dose date up to 31 days | Treatment-emergent adverse events (AEs) are defined as one or both of the following: * Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug. * Any AEs leading to premature discontinuation of study drug. |
| Number of Participants Experiencing Clinical Laboratory Abnormalities | First dose date up to 31 days | Treatment-emergent laboratory abnormalities reported as an adverse event (AE) or serious adverse event (SAE) are presented. Laboratory abnormalities that required medical or surgical intervention or led to study drug interruption, modification, or discontinuation were recorded as an AE or SAE, as applicable, and are reported here. Laboratory abnormalities without clinical significance were not recorded as AEs or SAEs and therefore, are not being reported. |
Countries
Germany, New Zealand, Romania, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in United States, Romania, Germany, and New Zealand. The first participant was screened on 19 March 2015. The last study visit occurred on 22 April 2016.
Pre-assignment details
91 participants were screened. No participants were enrolled in the severe hepatic impairment (cohort 2) arm.
Participants by arm
| Arm | Count |
|---|---|
| Moderate Hepatic Impairment (Cohort 1) Participants with moderate hepatic impairment received a single dose of eleclazine 30 mg (5 x 6 mg tablets) on Day 1. | 14 |
| Mild Hepatic Impairment (Cohort 3) Participants with mild hepatic impairment received a single dose of eleclazine 30 mg (5 x 6 mg tablets) on Day 1. | 14 |
| Normal Hepatic Function Participants with normal hepatic function received a single dose of eleclazine 30 mg (5 x 6 mg tablets) on Day 1. | 21 |
| Total | 49 |
Baseline characteristics
| Characteristic | Mild Hepatic Impairment (Cohort 3) | Normal Hepatic Function | Moderate Hepatic Impairment (Cohort 1) | Total |
|---|---|---|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 8.9 | 55 years STANDARD_DEVIATION 6.9 | 56 years STANDARD_DEVIATION 5.3 | 56 years STANDARD_DEVIATION 7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 9 Participants | 5 Participants | 15 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 12 Participants | 9 Participants | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 18 Participants | 12 Participants | 42 Participants |
| Region of Enrollment Germany | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Region of Enrollment New Zealand | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Region of Enrollment Romania | 4 Participants | 2 Participants | 0 Participants | 6 Participants |
| Region of Enrollment United States | 6 Participants | 16 Participants | 13 Participants | 35 Participants |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 4 Participants | 15 Participants |
| Sex: Female, Male Male | 10 Participants | 14 Participants | 10 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 | 0 / 21 |
| other Total, other adverse events | 6 / 14 | 8 / 14 | 3 / 21 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 21 |
Outcome results
Primary
PK Parameter: AUCinf of GS-623134 (Metabolite of Eleclazine)
AUCinf was defined as the concentration of drug extrapolated to infinite time (area under the plasma concentration versus time curve extrapolated to infinite time).
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48, 72, 96, 120 hours on Day 1 and approximately the same time in the morning as predose of Day 1 on Days 15, 29, 43, and 57
Population: Participants in the PK Analysis Set with available data were analyzed. Healthy control participants may participate in more than one cohorts.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Moderate Hepatic Impairment (Cohort 1) | PK Parameter: AUCinf of GS-623134 (Metabolite of Eleclazine) | 1880.0 h*ng/mL |
| Mild Hepatic Impairment (Cohort 3) | PK Parameter: AUCinf of GS-623134 (Metabolite of Eleclazine) | 1983.2 h*ng/mL |
| Normal Hepatic Function (Matched Control for Cohort 1) | PK Parameter: AUCinf of GS-623134 (Metabolite of Eleclazine) | 2326.2 h*ng/mL |
| Normal Hepatic Function (Matched Control for Cohort 3) | PK Parameter: AUCinf of GS-623134 (Metabolite of Eleclazine) | 2697.4 h*ng/mL |
Comparison: ANOVA appropriate for a parallel design was fit to the natural logarithmic transformation of GS-623134 AUCinf.90% CI: [45.11, 144.79]
90% CI: [47.83, 113.02]
Primary
PK Parameter: Cmax of Eleclazine
Cmax was defined as the maximum observed concentration of drug in plasma.
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48, 72, 96, 120 hours on Day 1 and approximately the same time in the morning as predose of Day 1 on Days 15, 29, 43, and 57
Population: Participants in the PK Analysis Set were analyzed. Healthy control participants may participate in more than one cohorts.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Moderate Hepatic Impairment (Cohort 1) | PK Parameter: Cmax of Eleclazine | 214.9 ng/mL |
| Mild Hepatic Impairment (Cohort 3) | PK Parameter: Cmax of Eleclazine | 338.1 ng/mL |
| Normal Hepatic Function (Matched Control for Cohort 1) | PK Parameter: Cmax of Eleclazine | 322.9 ng/mL |
| Normal Hepatic Function (Matched Control for Cohort 3) | PK Parameter: Cmax of Eleclazine | 331.3 ng/mL |
Comparison: ANOVA appropriate for a parallel design was fit to the natural logarithmic transformation of eleclazine Cmax.90% CI: [53.33, 83.04]
Comparison: ANOVA appropriate for a parallel design was fit to the natural logarithmic transformation of eleclazine Cmax.90% CI: [83.03, 125.45]
Primary
PK Parameter: Cmax of GS-623134 (Metabolite of Eleclazine)
Cmax was defined as the maximum observed concentration of drug in plasma.
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48, 72, 96, 120 hours on Day 1 and approximately the same time in the morning as predose of Day 1 on Days 15, 29, 43, and 57
Population: Participants in the PK Analysis Set with available data were analyzed. Healthy control participants may participate in more than one cohorts.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Moderate Hepatic Impairment (Cohort 1) | PK Parameter: Cmax of GS-623134 (Metabolite of Eleclazine) | 4.9 ng/mL |
| Mild Hepatic Impairment (Cohort 3) | PK Parameter: Cmax of GS-623134 (Metabolite of Eleclazine) | 7.3 ng/mL |
| Normal Hepatic Function (Matched Control for Cohort 1) | PK Parameter: Cmax of GS-623134 (Metabolite of Eleclazine) | 6.5 ng/mL |
| Normal Hepatic Function (Matched Control for Cohort 3) | PK Parameter: Cmax of GS-623134 (Metabolite of Eleclazine) | 10.2 ng/mL |
Comparison: ANOVA appropriate for a parallel design was fit to the natural logarithmic transformation of GS-623134 Cmax.90% CI: [50.65, 114.77]
Comparison: ANOVA appropriate for a parallel design was fit to the natural logarithmic transformation of GS-623134 Cmax.90% CI: [44.59, 113.25]
Primary
PK (Pharmacokinetic) Parameter: AUCinf of Eleclazine
AUCinf was defined as the concentration of drug extrapolated to infinite time (area under the plasma concentration versus time curve extrapolated to infinite time).
Time frame: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, 14, 24, 36, 48, 72, 96, 120 hours on Day 1 and approximately the same time in the morning as predose of Day 1 on Days 15, 29, 43, and 57
Population: PK Analysis Set included all enrolled participants who received at least one dose of eleclazine and had at least one evaluable PK concentration value reported by the PK laboratory for the corresponding analyte. Healthy control participants may participate in more than one cohorts.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Moderate Hepatic Impairment (Cohort 1) | PK (Pharmacokinetic) Parameter: AUCinf of Eleclazine | 42503.2 h*ng/mL |
| Mild Hepatic Impairment (Cohort 3) | PK (Pharmacokinetic) Parameter: AUCinf of Eleclazine | 50064.7 h*ng/mL |
| Normal Hepatic Function (Matched Control for Cohort 1) | PK (Pharmacokinetic) Parameter: AUCinf of Eleclazine | 57795.9 h*ng/mL |
| Normal Hepatic Function (Matched Control for Cohort 3) | PK (Pharmacokinetic) Parameter: AUCinf of Eleclazine | 39173.2 h*ng/mL |
Comparison: An analysis of variance (ANOVA) appropriate for a parallel design was fit to the natural logarithmic transformation of eleclazine AUCinf.90% CI: [41.92, 129.01]
Comparison: An analysis of variance (ANOVA) appropriate for a parallel design was fit to the natural logarithmic transformation of eleclazine AUCinf.90% CI: [73.57, 222.01]
Secondary
Number of Participants Experiencing Clinical Laboratory Abnormalities
Treatment-emergent laboratory abnormalities reported as an adverse event (AE) or serious adverse event (SAE) are presented. Laboratory abnormalities that required medical or surgical intervention or led to study drug interruption, modification, or discontinuation were recorded as an AE or SAE, as applicable, and are reported here. Laboratory abnormalities without clinical significance were not recorded as AEs or SAEs and therefore, are not being reported.
Time frame: First dose date up to 31 days
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moderate Hepatic Impairment (Cohort 1) | Number of Participants Experiencing Clinical Laboratory Abnormalities | Blood Creatinine Increased | 0 Participants |
| Moderate Hepatic Impairment (Cohort 1) | Number of Participants Experiencing Clinical Laboratory Abnormalities | Gamma-glutamyltransferase Increased | 0 Participants |
| Mild Hepatic Impairment (Cohort 3) | Number of Participants Experiencing Clinical Laboratory Abnormalities | Blood Creatinine Increased | 1 Participants |
| Mild Hepatic Impairment (Cohort 3) | Number of Participants Experiencing Clinical Laboratory Abnormalities | Gamma-glutamyltransferase Increased | 1 Participants |
| Normal Hepatic Function (Matched Control for Cohort 1) | Number of Participants Experiencing Clinical Laboratory Abnormalities | Blood Creatinine Increased | 0 Participants |
| Normal Hepatic Function (Matched Control for Cohort 1) | Number of Participants Experiencing Clinical Laboratory Abnormalities | Gamma-glutamyltransferase Increased | 0 Participants |
Secondary
Number of Participants Experiencing Treatment-Emergent Adverse Events
Treatment-emergent adverse events (AEs) are defined as one or both of the following: * Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug. * Any AEs leading to premature discontinuation of study drug.
Time frame: First dose date up to 31 days
Population: Safety Analysis Set included all enrolled participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Moderate Hepatic Impairment (Cohort 1) | Number of Participants Experiencing Treatment-Emergent Adverse Events | 6 Participants |
| Mild Hepatic Impairment (Cohort 3) | Number of Participants Experiencing Treatment-Emergent Adverse Events | 8 Participants |
| Normal Hepatic Function (Matched Control for Cohort 1) | Number of Participants Experiencing Treatment-Emergent Adverse Events | 3 Participants |