Clinical Trial Results:
Single-dose, open-label, randomized, 2-way crossover bioequivalence study of 10 mg granules for oral suspension rivaroxaban versus 10 mg tablets rivaroxaban under fasted condition in healthy subjects
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Summary
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EudraCT number |
2017-000648-16 |
Trial protocol |
DE |
Global end of trial date |
27 Oct 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
18 Aug 2018
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First version publication date |
18 Aug 2018
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Other versions |
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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 |
BAY59-7939/19365
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Bayer AG
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Sponsor organisation address |
Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,
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Public contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Scientific contact |
Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
27 Oct 2017
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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 |
27 Oct 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of the trial was to establish bioequivalence with respect to area under concentration versus time curve from zero to infinity after single dose administration (AUC), AUC from time zero to the last data point (AUC[0-tlast]) and maximum observed drug concentration (Cmax) of 10 milligrams (mg) granules for oral suspension versus 10 mg tablets rivaroxaban (BAY59-7939,Xarelto) when administered as single oral dose under fasting conditions.
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Protection of trial subjects |
The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
05 Jul 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Germany: 30
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Worldwide total number of subjects |
30
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EEA total number of subjects |
30
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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) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
30
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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 |
Study was conducted at one study center in Germany, between 05 July 2017 (first subject first visit) and 30 August 2017 (last subject last visit). | |||||||||
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Pre-assignment
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Screening details |
Overall, 66 subjects were screened, of these 36 subjects were screen failures: 3 subjects withdrew consent, 1 subject was not included due to physician’s decision and 32 subjects failed screening. A total of 30 subjects were randomized to treatment and all subjects completed the study. | |||||||||
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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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Treatment A-B | |||||||||
Arm description |
Subjects received a single oral dose of 10 mg rivaroxaban tablet in the fasted state on Day 1 (Treatment A) during intervention period 1; and then a single oral dose of 10 mg rivaroxaban oral suspension in the fasted state on Day 1 (Treatment B) during intervention period 2. A wash-out period of 7 days was maintained between the treatments. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Rivaroxaban
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Investigational medicinal product code |
BAY59-7939
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Other name |
Xarelto
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single oral dose of 10 mg rivaroxaban tablet in the fasted state on Day 1 (Treatment A).
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Investigational medicinal product name |
Rivaroxaban
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Investigational medicinal product code |
BAY59-7939
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Other name |
Xarelto
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Pharmaceutical forms |
Granules for oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single oral dose of 10 mg rivaroxaban oral suspension in the fasted state on Day 1 (Treatment B).
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Arm title
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Treatment B-A | |||||||||
Arm description |
Subjects received a single oral dose of 10 mg rivaroxaban oral suspension in the fasted state on Day 1 (Treatment B) during intervention period 1; and then a single oral dose of 10 mg rivaroxaban tablet in the fasted state on Day 1 (Treatment A) during intervention period 2. A wash-out period of 7 days was maintained between the treatments. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Rivaroxaban
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Investigational medicinal product code |
BAY59-7939
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Other name |
Xarelto
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Pharmaceutical forms |
Granules for oral suspension
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single oral dose of 10 mg rivaroxaban oral suspension in the fasted state on Day 1 (Treatment B).
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Investigational medicinal product name |
Rivaroxaban
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Investigational medicinal product code |
BAY59-7939
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Other name |
Xarelto
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received a single oral dose of 10 mg rivaroxaban tablet in the fasted state on Day 1 (Treatment A).
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Baseline characteristics reporting groups
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Reporting group title |
Treatment A-B
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Reporting group description |
Subjects received a single oral dose of 10 mg rivaroxaban tablet in the fasted state on Day 1 (Treatment A) during intervention period 1; and then a single oral dose of 10 mg rivaroxaban oral suspension in the fasted state on Day 1 (Treatment B) during intervention period 2. A wash-out period of 7 days was maintained between the treatments. | ||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Treatment B-A
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Reporting group description |
Subjects received a single oral dose of 10 mg rivaroxaban oral suspension in the fasted state on Day 1 (Treatment B) during intervention period 1; and then a single oral dose of 10 mg rivaroxaban tablet in the fasted state on Day 1 (Treatment A) during intervention period 2. A wash-out period of 7 days was maintained between the treatments. | ||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Treatment A-B
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Reporting group description |
Subjects received a single oral dose of 10 mg rivaroxaban tablet in the fasted state on Day 1 (Treatment A) during intervention period 1; and then a single oral dose of 10 mg rivaroxaban oral suspension in the fasted state on Day 1 (Treatment B) during intervention period 2. A wash-out period of 7 days was maintained between the treatments. | ||
Reporting group title |
Treatment B-A
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Reporting group description |
Subjects received a single oral dose of 10 mg rivaroxaban oral suspension in the fasted state on Day 1 (Treatment B) during intervention period 1; and then a single oral dose of 10 mg rivaroxaban tablet in the fasted state on Day 1 (Treatment A) during intervention period 2. A wash-out period of 7 days was maintained between the treatments. | ||
Subject analysis set title |
Safety Analysis Set (SAF)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
SAF included all subjects who received at least one dose of the study medication (N= 30).
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Subject analysis set title |
Pharmacokinetic Analysis Set (PKS)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
PKS included all subjects who completed all treatment periods, and for whom valid sets of pharmacokinetic samples were taken (N= 30).
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Subject analysis set title |
10 mg Rivaroxaban tablet
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received a single oral dose of 10 mg rivaroxaban tablet in the fasted state on Day 1 during any of the intervention periods (N= 30).
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Subject analysis set title |
10 mg Rivaroxaban oral suspension
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Subjects received a single oral dose of 10 mg rivaroxaban granules for oral suspension in the fasted state on Day 1 during any of the intervention periods (N = 30).
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End point title |
Area Under the Concentration Versus Time Curve From Zero to Infinity (AUC) of Rivaroxaban in Plasma After Single Dose Administration | ||||||||||||
End point description |
Area under the concentration versus time curve from zero to infinity of rivaroxaban in plasma after single dose administration was measured. Geometric mean and geometric coefficient of variation were reported.
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End point type |
Primary
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End point timeframe |
pre dose up to 72 hours post dose
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| Notes [1] - PKS [2] - PKS |
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Statistical analysis description |
Logarithms of the AUC were analyzed using analysis of variance (ANOVA) including sequence, subject (sequence), period, treatment effects. Based on these analyses point estimates (Least squares [LS] Mean) and confirmatory 90 percent confidence intervals for treatment ratio: 10 mg granules for oral suspension/tablet were calculated by re-transformation of the logarithmic results given by ANOVA. Database auto-calculates total number of subjects erroneously, analyzed number of subjects was 30.
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Comparison groups |
10 mg Rivaroxaban tablet v 10 mg Rivaroxaban oral suspension
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
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Parameter type |
LS mean | ||||||||||||
Point estimate |
1.0267
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
0.9841 | ||||||||||||
upper limit |
1.0712 | ||||||||||||
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End point title |
Area Under the Concentration Versus Time Curve From Time Zero to the Last Data Point Greater Than (>) Lower Limit Of Quantification (LLOQ) (AUC[0-tlast]) of Rivaroxaban in Plasma After Single Dose Administration | ||||||||||||
End point description |
Area under the concentration versus time curve from time zero to the last data point greater than (>) lower limit of quantification of rivaroxaban in plasma after single dose administration was measured. Geometric Mean and percentage of geometric coefficient of variation were reported.
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End point type |
Primary
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End point timeframe |
pre dose up to 72 hours post dose
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| Notes [3] - PKS [4] - PKS |
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Statistical analysis description |
Logarithms of the AUC(0-tlast) were analyzed using ANOVA including sequence, subject (sequence), period, treatment effects. Based on these analyses point estimates (LS mean) and confirmatory 90 percent confidence intervals for treatment ratio: 10 mg granules for oral suspension/tablet were calculated by re-transformation of the logarithmic results given by ANOVA. Database auto-calculates total number of subjects erroneously, analyzed number of subjects was 30.
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Comparison groups |
10 mg Rivaroxaban tablet v 10 mg Rivaroxaban oral suspension
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
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Parameter type |
LS mean | ||||||||||||
Point estimate |
1.0261
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
0.9805 | ||||||||||||
upper limit |
1.0738 | ||||||||||||
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End point title |
Maximum Observed Drug Concentration (Cmax) of Rivaroxaban in Plasma After Single Dose Administration | ||||||||||||
End point description |
Maximum observed drug concentration of rivaroxaban in plasma after single dose administration was measured. Geometric mean and percentage coefficient of variation were reported.
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End point type |
Primary
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End point timeframe |
pre dose up to 72 hours post dose
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| Notes [5] - PKS [6] - PKS |
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Statistical analysis title |
Statistical analysis 1 | ||||||||||||
Statistical analysis description |
Logarithms of the Cmax were analyzed using ANOVA including sequence, subject (sequence), period, treatment effects. Based on these analyses point estimates (LS mean) and confirmatory 90 percent confidence intervals for treatment ratio: 10 mg granules for oral suspension/tablet were calculated by re-transformation of the logarithmic results given by ANOVA. Database auto-calculates total number of subjects erroneously, analyzed number of subjects was 30.
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Comparison groups |
10 mg Rivaroxaban tablet v 10 mg Rivaroxaban oral suspension
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
Method |
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Parameter type |
LS mean | ||||||||||||
Point estimate |
1.1283
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
1.04 | ||||||||||||
upper limit |
1.224 | ||||||||||||
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End point title |
Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | |||||||||
End point description |
An adverse event (AE) was any untoward medical occurrence in subject who received study drug without regard to possibility of causal relationship. AEs that started or worsened after first administration of study medication up to 14 days after end of treatment with study medication were considered to be treatment emergent (TE).
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End point type |
Secondary
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End point timeframe |
from start of study drug administration up to 14 days after last study drug administration
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| Notes [7] - SAF [8] - SAF |
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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 the start of study drug administration until 14 days after last study drug administration
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
10 mg Rivaroxaban tablet
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Reporting group description |
Subjects received a single oral dose of 10 mg rivaroxaban tablet in the fasted state on Day 1 during any of the intervention periods. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
10 mg Rivaroxaban oral suspension
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Reporting group description |
Subjects received a single oral dose of 10 mg rivaroxaban granules for oral suspension in the fasted state on Day 1 during any of the intervention periods. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
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. | |||
| Occurrence of "±” in relation with geometric CV is auto generated. Decimal places were automatically truncated if last decimals is equals to zero. | |||
