Pharmacokinetic, Prolonged QTc Interval
Conditions
Keywords
QT/QTc Interval
Brief summary
The effect of multiple oral administration of two doses of CG5503 PR (prolonged release) compared to placebo on the electrical activity of the heart were investigated. The rationale to perform this study was to exclude any effect of CG5503 on the heart rhythm. This study was a randomised, double-blind, double-dummy, placebo- and moxifloxacin-controlled, 4-way cross-over study. Participants were given a combination of either CG5503 PR and placebo (medication with inactive ingredients which looks like the study drug) or moxifloxacin and placebo. Moxifloxacin was used as a positive control. It has consistently shown that it has an effect on the heart rhythm. Within 14 days prior to the first dosing, participants had a physical examination, a 12-lead electrocardiogram (ECG) was recorded and haematological, serological, biochemical, and urine analyses took place. A blood sample for optional genotyping of genes responsible for long QT syndrome was taken. During each dosing session, the participants were confined in the evening before baseline assessments were performed and stayed in the clinic until 48 hours after the last dosing. Study medication was administered on Day 1 and 2 in the morning (0.5 hours after breakfast) and in the evening (1.5 hours after dinner), and on Day 3 in the morning (0.5 hours after breakfast). Dosing was separated by at least 7 days between the last dosing of each period and the first dosing of next period. Interim analysis of ECG-data were performed after completion of 24 participants (group 1) with possible subsequent adjustment of sample size for group 2.
Interventions
DRUG100 mg CG5503 (tapentadol hydrochloride) PR tablet
100 mg CG5503 (tapentadol hydrochloride) PR tablet.
DRUGPlacebo matching CG5503 PR tablet
Matching placebo tablet to CG5503 PR tablet.
DRUGPlacebo matching moxifloxacin capsule
Matching placebo capsule to moxifloxacin capsule.
DRUG400 mg Moxifloxacin tablet (overencapsulated)
Overencapsulated 400 mg Moxifloxacin tablet.
Sponsors
Grünenthal GmbH
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Intervention model description
This study was a randomized, double-blind, double-dummy, placebo- and moxifloxacin-controlled, 4-way cross-over study. The randomization was in the ratio 1:1:1:1. In all treatments the amount of administered tablets and capsules were the same. At the lower dose step the amount of tablets/capsules was adjusted with matching placebos. All study procedures were the same, irrespective of whether active compound, positive control or placebo was administered.
Eligibility
Sex/Gender
ALL
Age
45 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Male or female Caucasian participants aged 45-65 years; * Body mass index (BMI) between 19 and 27 kilograms/square meter inclusive; * Participants must be in good health as determined by medical history, physical examination, 12-lead electrocardiogram , vital signs, and clinical laboratory parameters (serum/urine biochemistry, serology and haematology). Electrocardiogram (ECG) parameters and vitals signs must be in the ranges given in
Exclusion criteria
3-8 and 11-14, respectively) Minor deviations of laboratory values from the normal range may be accepted (except potassium and magnesium), if judged by the investigator to have no clinical relevance and if not considered to interfere with the study objectives. * Negative human immunodeficiency virus (HIV) 1/2 -antibodies, hepatitis B surface (HBs)-antigen, hepatitis B core (HBc)-antibodies and hepatitis C virus (HCV)-antibodies at the prestudy medical examination; * Negative blood beta-human chorionic gonadotropine (HCG)-test for women of child bearing potential; * Participants giving written consent to participate within this study; * Participants giving written consent for blood sampling to be genotyped for genes responsible for long QT syndrome (KCNQ1, human ether-a-go-go-related gene (HERG), SCN5A, KCNE1, KCNE2, KCNJ2).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The mean of corrected QT interval (QTc) differences on Day 3 at 3 to 7 hours to matched time points on Day 0 of the respective treatment period | Baseline (Day 0) to Day 3 | On Day 0 drug-free baseline 12-lead ECGs were recorded (in supine position after at least 10 minutes of rest) at time points corresponding to those on Day 3. On Day 3, 12-lead ECGs were recorded prior to and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 24 hours after dosing. A regression analysis was applied for each participant to obtain an individual correction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of treatment emergent adverse events | Day 1 to Day 5 | Number of adverse events and number of participants with adverse events. |
| Withdrawal symptoms: 5 categories of COWS scale, sum of scores (of 11 items) and changes to placebo in sum of scores | Day 4 and Day 5 | The clinical opiate withdrawal scale (COWS) assessment consisted of 11 questions which rated the severity of opiate withdrawal symptoms, including resting pulse rate, gastrointestinal upset, sweating, restlessness, pupil size, tremor, anxiety or irritability, bone or joint aches, gooseflesh skin, yawning, and runny nose or tearing. Each symptom was rated on a scale from 0 (not present) to 4 or 5 (most severe). The total score was calculated by summing the 11 individual scores. Scores from 0 to 4 are considered no withdrawal, from 5 to 12 mild withdrawal, from 13 to 24 moderate withdrawal, 25 to 36 moderately severe withdrawal and above 36 severe withdrawal. |
| Pharmacokinetic parameter: Cmax(4-6h) of CG5503 base after the first dose | Day 1 to Day 5 | Maximum serum concentration in the observed time interval between 4 and 6 hours \[Cmax(4-6h)\]. Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. Concentrations of CG5503 base in serum were determined by using validated High Performance Liquid Chromatography (HPLC) methods with fluorometric detection. |
| Pharmacokinetic parameter: tmax(4-6h) of CG5503 base after the first dose | Day 1 to Day 5 | Time to reach maximum serum concentration in the observed time interval between 4 and 6 hours \[tmax(4-6h)\]. Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. |
| Pharmacokinetic parameter: AUCss of CG5503 base after the last dose | Day 1 to Day 5 | Area under the concentration vs. time curve in dosing interval τ at steady state (AUCss). Blood samples for the determination of serum concentrations were taken at pre-dose and at up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. |
| Pharmacokinetic parameter: AUC of CG5503 base after the last dose | Day 1 to Day 5 | Area under the concentration vs. time curve (AUC) after the last dose. Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. |
| Pharmacokinetic parameter: AUCextr of CG5503 base after the last dose | Day 1 to Day 5 | Extrapolated part to infinity of AUC (AUCextr) after the last dose. Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. |
| Pharmacokinetic parameter: AUC%extr of CG5503 base after the last dose | Day 1 to Day 5 | Extrapolated part to infinity of AUC in percent (AUC%extr) after the last dose. |
| The differences of the QTc at each time point on Day 3 to the time matched QTc on Day 0 of each period | Baseline (Day 0) to Day 3 | In addition to the corrected QT by regression as described for the primary endpoint, QTc was calculated by the following formulas: Fridericia, Framingham, and Bazett. |
| Pharmacokinetic parameter: Css,max of CG5503 base after the last dose | Day 1 to Day 5 | Maximum observed serum concentration during dosing interval τ at steady state (Css,max). Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. |
| Pharmacokinetic parameter: Css,ave of CG5503 base after the last dose | Day 1 to Day 5 | Average serum concentration during dosing interval τ at steady state (Css,ave). Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. |
| Pharmacokinetic parameter: tss,max of CG5503 base after the last dose | Day 1 to Day 5 | Time to reach maximum serum concentration during dosing interval τ at steady state (tss,max). Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. |
| Pharmacokinetic parameter: λz of CG5503 base after the last dose | Day 1 to Day 5 | Apparent terminal elimination rate constant (λz) after the last dose. Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. |
| Pharmacokinetic parameter: t½,z of CG5503 base after the last dose | Day 1 to Day 5 | Apparent terminal half-life (t½,z) after the last dose. Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. |
| Pharmacokinetic parameter: CL/f of CG5503 base after the last dose | Day 1 to Day 5 | Apparent oral clearance at steady state (CL/f). Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. |
| Pharmacokinetic parameter: PTF (%) of CG5503 base after the last dose | Day 1 to Day 5 | Peak-trough fluctuation at steady state (PTF). Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. |
| Pharmacokinetic parameter: RA(Cmax) of CG5503 base after the last dose | Day 1 to Day 5 | Accumulation ratio (RA) calculated from Css,max at steady state and Cmax(4-6 hours) after single dosing. Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. |
| Pharmacokinetic parameter: Css,min of CG5503 base after the last dose | Day 1 to Day 5 | Minimum observed serum concentration during dosing interval τ at steady state (Css,min). Blood samples for the determination of serum concentrations were taken at pre-dose and up to 12 hours on Day 1, prior to the morning and the evening dose on Day 2 and before and up to 48 hours after the last drug administration. |
Countries
Germany
Outcome results
None listed