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出境医 / 临床实验 / Evaluation of the Effects of Multiple Doses of Cebranopadol on the Electrical Activity of the Heart in Healthy Subjects
Evaluation of the Effects of Multiple Doses of Cebranopadol on the Electrical Activity of the Heart in Healthy Subjects
Study Description
Brief Summary:
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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Prolonged QTc Interval Pharmacokinetic | Drug: 100 μg cebranopadol Drug: 200 μg cebranopadol Drug: 400 μg cebranopadol Drug: Placebo to cebranopadol encapsulated tablets Drug: 400 mg Moxifloxacin Drug: Placebo to moxifloxacin encapsulated tablets | Phase 1 |
Study Design
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 171 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Intervention Model Description: | Participants were randomized to 1 of 4 treatment groups on Day -3: The study included a nested cross-over design for participants in treatment group 3 (A, B). |
| Masking: | Double (Participant, Investigator) |
| Primary Purpose: | Treatment |
| Official Title: | Evaluation of the Effects of Multiple Therapeutic and Supratherapeutic Doses of Cebranopadol on Cardiac Repolarization in Healthy Subjects |
| Actual Study Start Date : | July 10, 2013 |
| Actual Primary Completion Date : | November 27, 2013 |
| Actual Study Completion Date : | November 27, 2013 |
Arms and Interventions
| Arm | Intervention/treatment |
|---|---|
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Experimental: Treatment Group 1: Cebranopadol
Supratherapeutic dose (1600 μg) of cebranopadol: Participants received placebo once a day for 2 days (Days -3 and -1); 200 μg of cebranopadol once a day for 3 days; 400 μg once a day for 3 days; 600 μg once a day for 3 days; 900 μg once a day for 3 days; 1300 μg once a day for 3 days; 1600 μg once a day for 14 days; and placebo once a day on the last dosing day. Participants received capsules under fasting conditions on Days -3, -1, 1, 29 and 30, and under fed conditions on all other dosing days. Participants received four encapsulated cebranopadol/ placebo tablets and 1 encapsulated moxifloxacin/ placebo tablet (5 capsules in total) on Day -3, Day -1, and from Day 1 to Day 30. Capsules were taken with 240 mL of water. |
Drug: 100 μg cebranopadol
Encapsulated 100 μg cebranopadol tablet.
Drug: 200 μg cebranopadol Encapsulated 200 μg cebranopadol tablet.
Drug: 400 μg cebranopadol Encapsulated 400 μg cebranopadol tablet.
Drug: Placebo to cebranopadol encapsulated tablets Matching placebo to cebranopadol encapsulated tablet.
Drug: Placebo to moxifloxacin encapsulated tablets Matching placebo to moxifloxacin (400 mg) encapsulated tablet.
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Experimental: Treatment Group 2: Cebranopadol
Therapeutic dose (600 μg) of cebranopadol: Participants received placebo once a day for the first 11 days (Days -3, -1 and 1-9); 200 μg of cebranopadol once a day for 3 days; 400 μg once a day for 3 days; 600 μg once a day for 14 days; and placebo once a day on the last dosing day. Participants received capsules under fasting conditions on Days -3, -1, 1, 29 and 30, and under fed conditions on all other dosing days. Participants received 4 encapsulated cebranopadol/ placebo tablets and 1 encapsulated moxifloxacin/ placebo tablet (5 capsules in total) on Day -3, Day -1, and from Day 1 to Day 30. Capsules were taken with 240 mL of water. |
Drug: 200 μg cebranopadol
Encapsulated 200 μg cebranopadol tablet.
Drug: 400 μg cebranopadol Encapsulated 400 μg cebranopadol tablet.
Drug: Placebo to cebranopadol encapsulated tablets Matching placebo to cebranopadol encapsulated tablet.
Drug: Placebo to moxifloxacin encapsulated tablets Matching placebo to moxifloxacin (400 mg) encapsulated tablet.
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Experimental: Treatment Group 3A: Placebo and Moxifloxacin
Placebo / Moxifloxacin: Participants received placebo once a day for 31 days (Days -3, -1 and 1-29) and moxifloxacin 400 mg once on the last dosing day. Participants received capsules under fasting conditions on Days -3, -1, 1, 29 and 30, and under fed conditions on all other dosing days. Participants received 4 encapsulated cebranopadol/ placebo tablets and 1 encapsulated moxifloxacin/ placebo tablet (5 capsules in total) on Day -3, Day -1, and from Day 1 to Day 30. Capsules were taken with 240 mL of water. |
Drug: Placebo to cebranopadol encapsulated tablets
Matching placebo to cebranopadol encapsulated tablet.
Drug: 400 mg Moxifloxacin Encapsulated 400 mg moxifloxacin tablet.
Drug: Placebo to moxifloxacin encapsulated tablets Matching placebo to moxifloxacin (400 mg) encapsulated tablet.
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Experimental: Treatment Group 3B: Moxifloxacin and Placebo
Moxifloxacin / Placebo: Participants received placebo once a day for 2 days (Days -3 and -1); moxifloxacin 400 mg once for 1 day; and placebo once a day for the following 29 days. Participants received capsules under fasting conditions on Days -3, -1, 1, 29 and 30, and under fed conditions on all other dosing days. Participants received four encapsulated cebranopadol/ placebo tablets and 1 encapsulated moxifloxacin/ placebo tablet (5 capsules in total) on Day -3, Day -1, and from Day 1 to Day 30. Capsules were taken with 240 mL of water. |
Drug: Placebo to cebranopadol encapsulated tablets
Matching placebo to cebranopadol encapsulated tablet.
Drug: 400 mg Moxifloxacin Encapsulated 400 mg moxifloxacin tablet.
Drug: Placebo to moxifloxacin encapsulated tablets Matching placebo to moxifloxacin (400 mg) encapsulated tablet.
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Outcome Measures
Primary Outcome Measures :
- QTcNi change from time-matched baseline measurement on Day -1 to Day 29 - supported sitting position [ Time Frame: Day -1 up to Day 29 ]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.
Secondary Outcome Measures :
- QTcNi change from time-matched baseline measurement on Day -1 to Day 29 - supine position [ Time Frame: Day -1 up to Day 29 ]Largest time-matched mean difference between cebranopadol and placebo in supine QTcNi change from time-matched baseline measurement on Day -1.
- QTcF change from time-matched baseline measurement on Day -1 to Day 29 - sitting position [ Time Frame: Day -1 up to Day 29 ]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.
- QTcF change from time-matched baseline measurement on Day -1 to Day 29 - supine position [ Time Frame: Day -1 up to Day 29 ]Largest time-matched mean difference between cebranopadol and placebo in supine QTcF change from time-matched baseline measurement on Day -1.
- Pharmacokinetic parameter: AUC0-tau,ss of cebranopadol [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: AUC0-tau,ss of M2 (7-hydroxy-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: AUC0-tau,ss of M3 (N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: AUC0-tau,ss of M6 (7-hydroxy N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: AUC0-t of cebranopadol [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: AUC0-t of M2 (7-hydroxy-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: AUC0-t of M3 (N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: AUC0-t of M6 (7-hydroxy N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Cav,ss of cebranopadol [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Cav,ss of M2 (7-hydroxy-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Cav,ss of M3 (N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Cav,ss of M6 (7-hydroxy N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Cmax,ss of cebranopadol [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Cmax,ss of M2 (7-hydroxy-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Cmax,ss of M3 (N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Cmax,ss of M6 (7-hydroxy N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Cmin,ss of cebranopadol [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Cmin,ss of M2 (7-hydroxy-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Cmin,ss of M3 (N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Cmin,ss of M6 (7-hydroxy N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Fluctuation of cebranopadol [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Fluctuation of M2 (7-hydroxy-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Fluctuation of M3 (N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Fluctuation of M6 (7-hydroxy N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Swing of cebranopadol [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Swing of M2 (7-hydroxy-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Swing of M3 (N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Swing of M6 (7-hydroxy N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: tmax of cebranopadol [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: tmax of M2 (7-hydroxy-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: tmax of M3 (N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: tmax of M6 (7-hydroxy N-desmethyl-GRT6005) [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: AUC0-inf of moxifloxacin [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: AUC0-t of moxifloxacin [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: Cmax of moxifloxacin [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: t1/2 of moxifloxacin [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
- Pharmacokinetic parameter: tmax of moxifloxacin [ Time Frame: Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 14, 24, 48, 72, and 96 hours post-dose ]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.
Eligibility Criteria
| Ages Eligible for Study: | 18 Years to 45 Years (Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
Criteria
Inclusion Criteria:
- Sign the informed consent form (ICF) and have the mental capability to understand it.
- Be a healthy male or female, aged 18 through 45 years, inclusive.
- If female, have a negative result from a serum pregnancy test at screening and a negative result from a serum or urine pregnancy test on Day -4.
- If male, agree to use an effective method of contraception (ie, condom plus diaphragm with spermicide or condom plus spermicide) and not have their partners become pregnant throughout the study, or have been sterilized for at least 1 year (with supporting documentation of the absence of sperm in the ejaculate postvasectomy).
- If female of childbearing potential, agree to use an effective method of contraception (ie, condom plus diaphragm with spermicide, condom plus spermicide, or nonhormonal intrauterine device) and not become pregnant throughout the study. Females who are at least 2-years postmenopausal (with supporting documentation from an obstetrician/gynecologist) or who have had tubal ligation or hysterectomy (with supporting documentation from the physician who performed the surgery) will not be considered to be of childbearing potential.
- Be nonsmoking (never smoked or have not smoked within the previous 2 years).
- Have a body mass index (BMI) greater than or equal to 18 kilograms per square meter and less than or equal to 30 kilograms per square meter.
- Have a sitting pulse rate greater than or equal to 50 beats per minute (bpm) and less than or equal to 100 bpm during the vital sign assessment at screening.
Exclusion Criteria:
- Known hypersensitivity to cebranopadol, other opioids, or moxifloxacin or other fluoroquinolone antibiotics.
- Clinically significant disease state, in the opinion of the examining physician, in any body system.
- Sitting systolic blood pressure (BP) greater than or equal to 140 millimeters mercury (mm Hg) or less than or equal to 90 mm Hg or sitting diastolic BP greater than or equal to 90 mm Hg or less than or equal to 50 mm Hg at screening.
- Abnormal electrocardiogram (ECG) results thought to be potentially clinically significant (PCS), or QT prolongation (QTcF greater than or equal to 450 milliseconds (msec) or uncorrected QT greater than or equal to 500 msec) according to the Investigator.
- History of cardiovascular disease including but not limited to long QT syndrome (or family history of long QT syndrome), cardiac arrhythmia, orthostatic hypotension, and coronary artery or valvular disease.
- Positive test results for anti-human immunodeficiency virus type 1, hepatitis B surface antigen, hepatitis B core antibodies, or anti-hepatitis C virus at screening.
- Abnormal and clinically significant results on medical history, physical examination, serum chemistry, hematology, or urinalysis.
- History of alcohol or other substance abuse within the previous 5 years.
- Positive urine drug screen test results for benzoylecgonine (cocaine), methadone, barbiturates, amphetamines, benzodiazepines, alcohol, cannabinoids, opiates, phencyclidine, or cotinine at screening or Day -4.
- Have taken opioids within the past 1 month.
- Participation in any other clinical investigation using an experimental drug requiring repeated blood or plasma draws within 60 days of investigational product administration.
- Participation in a blood or plasma donation program within 60 or 30 days, respectively, of investigational product administration.
- Consumption of caffeine products within 48 hours or any grapefruit-containing products or Seville oranges within 14 days or consumption of alcohol or poppy seeds within 72 hours before administration of investigational product.
- Consumption of beverages or food containing quinine (bitter lemon, tonic water) within 14 days before administration of investigational product until discharge from the study center.
- Have any clinical condition that might affect the absorption, distribution, biotransformation, or excretion of cebranopadol or moxifloxacin.
- Employee, or immediate relative of an employee, of Forest Laboratories, Inc. or Grünenthal GmbH, any of its affiliates or partners, or the study center.
- Taken any concomitant medications (including over-the-counter medications) within 14 days or hormonal drug products within 30 days before administration of investigational product.
- Previously taken cebranopadol or previously participated in an investigational study of cebranopadol.
- Breastfeeding.
- Responses to the Columbia-Suicide Severity Rating Scale (C-SSRS) that indicate any current suicidal ideation or a history of active suicidal ideation or suicide attempts.
- Suicidal risk based on the opinion of the principal investigator (or appropriately trained designee).
Contacts and Locations
Locations
| United States, Wisconsin | |
| US001 Contract research organization | |
| West Bend, Wisconsin, United States, 53095 | |
Sponsors and Collaborators
Grünenthal GmbH
Forest Laboratories
Investigators
| Study Director: | Study Director Grünenthal | Grünenthal GmbH |
| Tracking Information | |||||
|---|---|---|---|---|---|
| First Submitted Date ICMJE | May 20, 2019 | ||||
| First Posted Date ICMJE | May 21, 2019 | ||||
| Last Update Posted Date | May 23, 2019 | ||||
| Actual Study Start Date ICMJE | July 10, 2013 | ||||
| Actual Primary Completion Date | November 27, 2013 (Final data collection date for primary outcome measure) | ||||
| Current Primary Outcome Measures ICMJE |
QTcNi change from time-matched baseline measurement on Day -1 to Day 29 - supported sitting position [ Time Frame: Day -1 up to Day 29 ] 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.
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| Original Primary Outcome Measures ICMJE | Same as current | ||||
| Change History | |||||
| Current Secondary Outcome Measures ICMJE |
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| Original Secondary Outcome Measures ICMJE | Same as current | ||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||
| Descriptive Information | |||||
| Brief Title ICMJE | Evaluation of the Effects of Multiple Doses of Cebranopadol on the Electrical Activity of the Heart in Healthy Subjects | ||||
| Official Title ICMJE | Evaluation of the Effects of Multiple Therapeutic and Supratherapeutic Doses of Cebranopadol on Cardiac Repolarization in Healthy Subjects | ||||
| Brief Summary |
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. |
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| Detailed Description | Not Provided | ||||
| Study Type ICMJE | Interventional | ||||
| Study Phase ICMJE | Phase 1 | ||||
| Study Design ICMJE | Allocation: Randomized Intervention Model: Parallel Assignment Intervention Model Description: Participants were randomized to 1 of 4 treatment groups on Day -3: The study included a nested cross-over design for participants in treatment group 3 (A, B). Masking: Double (Participant, Investigator)Primary Purpose: Treatment |
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| Condition ICMJE |
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| Intervention ICMJE |
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| Study Arms ICMJE |
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| Publications * | Not Provided | ||||
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||
| Recruitment Status ICMJE | Completed | ||||
| Actual Enrollment ICMJE |
171 | ||||
| Original Actual Enrollment ICMJE | Same as current | ||||
| Actual Study Completion Date ICMJE | November 27, 2013 | ||||
| Actual Primary Completion Date | November 27, 2013 (Final data collection date for primary outcome measure) | ||||
| Eligibility Criteria ICMJE |
Inclusion Criteria:
Exclusion Criteria:
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| Sex/Gender ICMJE |
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| Ages ICMJE | 18 Years to 45 Years (Adult) | ||||
| Accepts Healthy Volunteers ICMJE | Yes | ||||
| Contacts ICMJE | Contact information is only displayed when the study is recruiting subjects | ||||
| Listed Location Countries ICMJE | United States | ||||
| Removed Location Countries | |||||
| Administrative Information | |||||
| NCT Number ICMJE | NCT03958123 | ||||
| Other Study ID Numbers ICMJE | GRT-PK-12 | ||||
| Has Data Monitoring Committee | No | ||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement ICMJE |
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| Responsible Party | Grünenthal GmbH | ||||
| Study Sponsor ICMJE | Grünenthal GmbH | ||||
| Collaborators ICMJE | Forest Laboratories | ||||
| Investigators ICMJE |
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| PRS Account | Grünenthal GmbH | ||||
| Verification Date | May 2019 | ||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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