The objective of this study was to evaluate the effects of cebranopadol (GRT6005) on the electrical activity of the heart in healthy participants. The study consisted of a screening period within 21 days before the first dose of investigational medicinal product (IMP) (between Day -25 and Day -4) during which informed consent was obtained and the general suitability of the participants for the trial was assessed according to the inclusion/exclusion criteria. Participants were confined to the trial site from 4 days before first IMP dosing on Day 1 to 4 days after last IMP dosing on Day 30. During this period, multiple-doses of cebranopadol or matching placebo and a single-dose of moxifloxacin or matching placebo were administered. Moxifloxacin was used as a positive control. It has consistently shown that it has an effect on the heart rhythm. Continuous 12-lead ECGs were recorded at defined time points. Multiple blood and urine samples were drawn for pharmacokinetic evaluations and safety laboratory monitoring (hematology, chemistry, and urinalysis). Additional safety evaluations included recording of adverse events, vital signs (systolic and diastolic blood pressure, pulse rate, respiration rate, body temperature, and weight), oxygen saturation, standard 12-lead ECG, Clinical Opiate Withdrawal Scale (COWS) assessment, and Columbia-Suicide Severity Rating Scale (C-SSRS) assessment. An End-of-Trial Visit was performed on Day 34, or within 7 days after the last pharmacokinetic sample on Day 34, or at early withdrawal.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
171
Encapsulated 100 μg cebranopadol tablet.
Encapsulated 200 μg cebranopadol tablet.
Encapsulated 400 μg cebranopadol tablet.
Matching placebo to cebranopadol encapsulated tablet.
Encapsulated 400 mg moxifloxacin tablet.
Matching placebo to moxifloxacin (400 mg) encapsulated tablet.
US001 Contract research organization
West Bend, Wisconsin, United States
QTcNi change from time-matched baseline measurement on Day -1 to Day 29 - supported sitting position
Largest time-matched mean difference between cebranopadol and placebo in supported sitting QT interval corrected for heart rate using an individual correction (QTcNi) change from time-matched baseline measurement on Day -1.
Time frame: Day -1 up to Day 29
QTcNi change from time-matched baseline measurement on Day -1 to Day 29 - supine position
Largest time-matched mean difference between cebranopadol and placebo in supine QTcNi change from time-matched baseline measurement on Day -1.
Time frame: Day -1 up to Day 29
QTcF change from time-matched baseline measurement on Day -1 to Day 29 - sitting position
Largest time-matched mean difference between cebranopadol and placebo in supported sitting QT interval corrected for heart rate using the Fridericia formula (QTcF) change from time-matched baseline measurement on Day -1.
Time frame: Day -1 up to Day 29
QTcF change from time-matched baseline measurement on Day -1 to Day 29 - supine position
Largest time-matched mean difference between cebranopadol and placebo in supine QTcF change from time-matched baseline measurement on Day -1.
Time frame: Day -1 up to Day 29
Pharmacokinetic parameter: AUC0-tau,ss of cebranopadol
Area under the plasma concentration versus time curve from time 0 to the end of the dosing interval, tau, at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: AUC0-tau,ss of M2 (7-hydroxy-GRT6005)
Area under the plasma concentration versus time curve from time 0 to the end of the dosing interval, tau, at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: AUC0-tau,ss of M3 (N-desmethyl-GRT6005)
Area under the plasma concentration versus time curve from time 0 to the end of the dosing interval, tau, at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: AUC0-tau,ss of M6 (7-hydroxy N-desmethyl-GRT6005)
Area under the plasma concentration versus time curve from time 0 to the end of the dosing interval, tau, at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: AUC0-t of cebranopadol
Area under the plasma concentration versus time curve from time 0 to time t after the last dose. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: AUC0-t of M2 (7-hydroxy-GRT6005)
Area under the plasma concentration versus time curve from time 0 to time t after the last dose. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: AUC0-t of M3 (N-desmethyl-GRT6005)
Area under the plasma concentration versus time curve from time 0 to time t after the last dose. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: AUC0-t of M6 (7-hydroxy N-desmethyl-GRT6005)
Area under the plasma concentration versus time curve from time 0 to time t after the last dose. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Cav,ss of cebranopadol
Average plasma drug concentration at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Cav,ss of M2 (7-hydroxy-GRT6005)
Average plasma drug concentration at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Cav,ss of M3 (N-desmethyl-GRT6005)
Average plasma drug concentration at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Cav,ss of M6 (7-hydroxy N-desmethyl-GRT6005)
Average plasma drug concentration at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Cmax,ss of cebranopadol
Maximum plasma drug concentration at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Cmax,ss of M2 (7-hydroxy-GRT6005)
Maximum plasma drug concentration at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Cmax,ss of M3 (N-desmethyl-GRT6005)
Maximum plasma drug concentration at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Cmax,ss of M6 (7-hydroxy N-desmethyl-GRT6005)
Maximum plasma drug concentration at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Cmin,ss of cebranopadol
Minimum plasma drug concentration at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Cmin,ss of M2 (7-hydroxy-GRT6005)
Minimum plasma drug concentration at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Cmin,ss of M3 (N-desmethyl-GRT6005)
Minimum plasma drug concentration at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Cmin,ss of M6 (7-hydroxy N-desmethyl-GRT6005)
Minimum plasma drug concentration at steady state. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Fluctuation of cebranopadol
The difference between Cmin and Cmax standardized to Cavg, within 1 dosing interval. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Fluctuation of M2 (7-hydroxy-GRT6005)
The difference between Cmin and Cmax standardized to Cavg, within 1 dosing interval. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Fluctuation of M3 (N-desmethyl-GRT6005)
The difference between Cmin and Cmax standardized to Cavg, within 1 dosing interval. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Fluctuation of M6 (7-hydroxy N-desmethyl-GRT6005)
The difference between Cmin and Cmax standardized to Cavg, within 1 dosing interval. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Swing of cebranopadol
The difference between Cmin and Cmax standardized to Cmin, within 1 dosing interval. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Swing of M2 (7-hydroxy-GRT6005)
The difference between Cmin and Cmax standardized to Cmin, within 1 dosing interval. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Swing of M3 (N-desmethyl-GRT6005)
The difference between Cmin and Cmax standardized to Cmin, within 1 dosing interval. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Swing of M6 (7-hydroxy N-desmethyl-GRT6005)
The difference between Cmin and Cmax standardized to Cmin, within 1 dosing interval. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: tmax of cebranopadol
Time of maximum plasma drug concentration. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: tmax of M2 (7-hydroxy-GRT6005)
Time of maximum plasma drug concentration. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: tmax of M3 (N-desmethyl-GRT6005)
Time of maximum plasma drug concentration. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: tmax of M6 (7-hydroxy N-desmethyl-GRT6005)
Time of maximum plasma drug concentration. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for cebranopadol and its metabolites were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: AUC0-inf of moxifloxacin
Area under the plasma concentration versus time curve from time 0 to infinity. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for moxifloxacin were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: AUC0-t of moxifloxacin
Area under the first moment of the plasma concentration versus time curve from time 0 to time t. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for moxifloxacin were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: Cmax of moxifloxacin
Maximum plasma drug concentration. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for moxifloxacin were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: t1/2 of moxifloxacin
Terminal half-life. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for moxifloxacin were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
Pharmacokinetic parameter: tmax of moxifloxacin
Time of maximum plasma drug concentration. PK blood samples were collected before administration of the IMP and up to 96 hours after dosing; 32 PK blood samples were obtained from each participant. Plasma concentrations for moxifloxacin were determined using validated high-performance liquid chromatography-tandem mass spectrometry bioanalytical assays.
Time frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose
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