Clinical Trial Results:
Multiple-Dose Study to Evaluate the Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Apixaban in Pediatric Subjects with an Indwelling Central Venous Catheter
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Summary
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EudraCT number |
2010-024597-19 |
Trial protocol |
BE NL Outside EU/EEA |
Global end of trial date |
05 Oct 2012
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Results information
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Results version number |
v1 |
This version publication date |
06 Jan 2017
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First version publication date |
06 Jan 2017
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Other versions |
v2 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
CV185-079
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01195727 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Bristol-Myers Squibb
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Sponsor organisation address |
Chaussée de la Hulpe 185, Brussels, Belgium, 1170
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Public contact |
EU Study Start-Up Unit, Bristol-Myers Squibb, clinical.trials@bms.com
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Scientific contact |
EU Study Start-Up Unit, Bristol-Myers Squibb, clinical.trials@bms.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000183-PIP01-08 EMEA-000183-PIP02-12 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
05 Oct 2012
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
05 Oct 2012
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The main objective of this study is primarily to study the pharmacokinetics and pharmacodynamics of Apixaban in pediatric subjects with a central venous cathether.
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Protection of trial subjects |
The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
19 Jul 2011
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 12
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Country: Number of subjects enrolled |
Mexico: 1
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Worldwide total number of subjects |
13
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
2
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Adolescents (12-17 years) |
11
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 13 subjects were enrolled, and 8 received study treatment. 5 subjects were enrolled but not treated due to screen failures. | ||||||||||||||||||
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Period 1
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Period 1 title |
Overall study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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4A (0.60 mg/m2 Apixaban) | ||||||||||||||||||
Arm description |
Subjects were administered 0.60 mg/m2 Apixaban, twice daily (every 12 hours with a +/- 1 hour window), for 10 days (Day 1 through Day 10). | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Apixaban
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Investigational medicinal product code |
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Other name |
Eliquis
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Apixaban oral solution (0.4 mg/mL) was administered twice daily for 10 days.
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Arm title
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5A (0.66 mg/m2 Apixaban) | ||||||||||||||||||
Arm description |
Subjects were administered 0.66 mg/m2 Apixaban, twice daily (every 12 hours with a +/- 1 hour window), for 10 days (Day 1 through Day 10). | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Apixaban
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Investigational medicinal product code |
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Other name |
Eliquis
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Pharmaceutical forms |
Oral solution
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Routes of administration |
Oral use
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Dosage and administration details |
Apixaban oral solution (0.4 mg/mL) was administered by mouth via graduated dosing syringe, twice daily, for 10 days.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Of the 13 subjects enrolled, only 8 received treatment. |
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Baseline characteristics reporting groups
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Reporting group title |
4A (0.60 mg/m2 Apixaban)
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Reporting group description |
Subjects were administered 0.60 mg/m2 Apixaban, twice daily (every 12 hours with a +/- 1 hour window), for 10 days (Day 1 through Day 10). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
5A (0.66 mg/m2 Apixaban)
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Reporting group description |
Subjects were administered 0.66 mg/m2 Apixaban, twice daily (every 12 hours with a +/- 1 hour window), for 10 days (Day 1 through Day 10). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
4A (0.60 mg/m2 Apixaban)
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Reporting group description |
Subjects were administered 0.60 mg/m2 Apixaban, twice daily (every 12 hours with a +/- 1 hour window), for 10 days (Day 1 through Day 10). | ||
Reporting group title |
5A (0.66 mg/m2 Apixaban)
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Reporting group description |
Subjects were administered 0.66 mg/m2 Apixaban, twice daily (every 12 hours with a +/- 1 hour window), for 10 days (Day 1 through Day 10). | ||
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End point title |
Geometric Mean of Model-Estimated Individual Steady-State Cmax Parameters [1] | ||||||||||||
End point description |
A Population Pharmacokinetics (PPK) model was developed using plasma apixaban concentration versus time data. Maximum estimated plasma concentration at steady state (Cmax) in each subject was derived from model-estimated population and individual PK parameters (eg: CL/F, Vc/F, KA). Geometric means were reported in nanograms per milliliter (ng/mL) along with the coefficient of variation (%CV). All treated subjects were included in the analysis.
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End point type |
Primary
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End point timeframe |
Apixaban concentrations were collected at 9 time points from Days 1 through 11.
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only summary statistics were planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Geometric Mean of Model-Estimated Steady-State AUC(TAU) of Apixaban [2] | ||||||||||||
End point description |
A Population Pharmacokinetics (PPK) model was developed using plasma apixaban concentration versus time data. Model-estimated population and individual PK parameters (eg: CL/F, Vc/F, KA) were used to derive the steady-state estimated area under the plasma concentration time curve for one dosing interval [AUC(TAU)] in each subject. Geometric means were reported in nanogram hours per milliliter (ng*hr/mL) along with the coefficient of variation (%CV). All treated subjects were included in the analysis.
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End point type |
Primary
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End point timeframe |
Apixaban concentrations were collected at 9 time points from Days 1 through 11.
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only summary statistics were planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Geometric Mean of Model-Estimated Individual Steady-State Cmin parameters [3] | ||||||||||||
End point description |
A Population Pharmacokinetics (PPK) model was developed using plasma apixaban concentration versus time data. Minimum estimated plasma concentration at steady state (Cmin) in each subject was derived from model-estimated population and individual PK parameters (eg: CL/F, Vc/F, KA) . Geometric means were reported in nanograms per milliliter (ng/mL) along with the coefficient of variation (%CV). All treated subjects were included in the analysis.
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End point type |
Primary
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End point timeframe |
Apixaban concentrations were collected at 9 time points from Days 1 through 11.
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only summary statistics were planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Median Time to Model-Estimated Steady-State Plasma Concentration Maximum (Tmax) [4] | ||||||||||||
End point description |
A population PK (PPK) model was developed using plasma apixaban concentration versus time data. Model-estimated population and individual PK parameters (eg. CL/F, Vc/F, KA) were used to derive time to maximum steady-state concentration (Tmax) of Apixaban in each subject. Medians were reported in hours post-dose at steady state. All treated subjects were included in the analysis.
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End point type |
Primary
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End point timeframe |
Apixaban concentrations were collected at 9 time points from Days 1 through 11.
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only summary statistics were planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Geometric Mean Absorption Rate (Ka) of Apixaban [5] | ||||||||||||
End point description |
The absorption rate was defined as the rate at which Apixaban entered the blood stream. A population PK (PPK) model was developed using plasma apixaban concentration versus time data. Subject PK parameter values were derived using a nonlinear mixed-effects (“population”) compartmental model. Geometric means for the individual estimated absorption rate (Ka) parameters were presented in (1/h) along with the coefficient of variation (%CV). All treated subjects were included in the analysis.
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End point type |
Primary
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End point timeframe |
Apixaban concentrations were collected at 9 time points from Days 1 through 11.
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only summary statistics were planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Geometric Mean of Apparent Plasma Clearance Rate (CL/F) of Apixaban [6] | ||||||||||||
End point description |
Apparent plasma clearance after extravascular administration (CL/F) of Apixaban was estimated for each subject. A population PK (PPK) model was developed using plasma apixaban concentration versus time data. Subject PK parameter values were derived using a nonlinear mixed-effects (“population”) compartmental model. Geometric means for the individual estimated apparent oral clearance (CL/F) parameters were presented in (L/h) along with the coefficient of variation (%CV). All treated subjects were included in the analysis.
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End point type |
Primary
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End point timeframe |
Apixaban concentrations were collected at 9 time points from Days 1 through 11.
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only summary statistics were planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Geometric mean of apparent volume of distribution of the central compartment (Vc/F) [7] | ||||||||||||
End point description |
A population PK (PPK) model was developed using plasma apixaban concentration versus time data. Subject PK parameter values were derived using a nonlinear mixed-effects (“population”) compartmental model. Geometric means for the individual estimated apparent volume of distribution of the central compartment (Vc/F) were presented in liters along with the coefficient of variation (%CV). All treated subjects were included in the analysis.
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End point type |
Primary
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End point timeframe |
Apixaban concentrations were collected at 9 time points from Days 1 through 11.
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only summary statistics were planned for this endpoint |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mean maximum estimated anti-Xa activity at steady state (AXAmax) | ||||||||||||
End point description |
A Population Pharmacokinetic-Pharmacodynamic (PPK-PD) model was developed for anti-FXa activity vs. apixaban concentration and used to estimate the maximum anti-FXa activity at steady state (AXAmax). Means were reported in Low Molecular Weight Heparin activity units (IU/mL). All treated subjects were included in the analysis.
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End point type |
Secondary
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End point timeframe |
Blood draws for anti-Xa activity were performed at 6 time points from Days 1 through 7.
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Mean minimum estimated anti-Xa activity at steady state (AXAmin) | ||||||||||||
End point description |
A Population Pharmacokinetic-Pharmacodynamic (PPK-PD) model was developed for anti-FXa activity vs. apixaban concentration and used to estimate the minimum anti-FXa activity at steady state (AXAmin). Means are reported in Low Molecular Weight Heparin activity units (IU/mL). All treated subjects were included in the analysis.
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End point type |
Secondary
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End point timeframe |
Blood draws for anti-Xa activity were performed at 6 time points from Days 1 through 7.
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From first dose to 90 days after last dose
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
15.1
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Reporting groups
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Reporting group title |
4A (0.60 mg/m2 Apixaban)
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Reporting group description |
Subjects were administered 0.60 mg/m2 Apixaban, twice daily (every 12 hours with a +/- 1 hour window), for 10 days (Day 1 through Day 10). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
5A (0.66 mg/m2 Apixaban)
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Reporting group description |
Subjects were administered 0.66 mg/m2 Apixaban, twice daily (every 12 hours with a +/- 1 hour window), for 10 days (Day 1 through Day 10). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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19 Aug 2010 |
The main purpose of this amendment is to update the enrollment scheme to state that data from 3 subjects in Group 2B is reviewed prior to enrolling neonates in Group 1. In addition, updates have been made in regard to prohibited and restricted use of treatments and provide additional supporting information to the rational pertaining to the enrollment of neonates. |
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27 Dec 2010 |
The main purpose of this amendment is to update the stopping rules for individual subject discontinuation as well as criteria for when the study would be terminated. Other updates include the addition of language that the sponsor in conjunction with the investigators will review data at selected milestones throughout the study; the addition of recommended treatment guidelines for bleeding or suspected bleeding events, and language to allow dose adjustments to be implemented on the morning of Day 3. |
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11 Dec 2011 |
The main purpose of this amendment is to update the Exclusion Criteria relating to positive urine screen for drugs of abuse for adolescents allowing medical monitor approval; allowance of concomitant medications during the study; Remove need for duplicate PD sample on Day 1, 0 hour, deletion of the statement that
plasma samples will be archived for potential metabolite analysis; deletion of the statement that subjects who receive placebo in any panel will be pooled into a single placebo group. Other updates include a change of the Study Directors and editorial updates. |
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25 Jun 2012 |
The main purpose of this amendment is to update the Study Design section, whereas only Adolescents 12 years to <18 years (Cohorts 5A
& 5B) will continue to be enrolled in the study. Due to slow recruitment rate of younger age groups enrollment of subjects younger than 12 years was terminated after two (2) subjects from Cohort 4A were enrolled (Age Group 6 years to <12 years; Dose: 0.60 mg/m2). The number of total subjects in the study will change
from 60 to 12 (from Cohorts 5A & 5B). Reference to any other Cohorts, in the study design, has been removed. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||||||
| None reported | |||||||
