Clinical Trial Results:
A phase II multicenter trial with Rivaroxaban in the treatment of livedoid vasculopathy assessing the pain on a visual analog scale (VAS)
Summary
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EudraCT number |
2012-000108-13 |
Trial protocol |
DE |
Global end of trial date |
11 Sep 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Jul 2016
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First version publication date |
29 Jul 2016
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Other versions |
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 |
UKM10_0018
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Universitätsklinikum Münster
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Sponsor organisation address |
Albert-Schweitzer-Campus 1, Gebäude D5, Münster, Germany, 48149
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Public contact |
Klinik für Hautkrankheiten, Universitätsklinikum Münster, tobias.goerge@ukmuenster.de
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Scientific contact |
Klinik für Hautkrankheiten, Universitätsklinikum Münster, tobias.goerge@ukmuenster.de
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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 |
11 Sep 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
11 Sep 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Sep 2014
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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 main objective of the trial is the statistical evaluation of the therapeutic effects of rivaroxaban in patients with livedoid vasculopathy.
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Protection of trial subjects |
The study was conducted in accordance with the Declaration of Helsinki and the ICH Guidelines in Good Clinical Practice. The study was not started before the competent ethics committee had given a favorable opinion. Written informed consent was obtained from all patients and the study was only conducted as approved by the Ethics committee and the competent authority. Amendments were only implemented after approval.
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Background therapy |
Enoxaparin (1 mg/kg bodyweight) was allowed as backup medication in case of treatment failure. | ||
Evidence for comparator |
Not applicable. | ||
Actual start date of recruitment |
28 Dec 2012
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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: 28
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Worldwide total number of subjects |
28
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EEA total number of subjects |
28
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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) |
18
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From 65 to 84 years |
10
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85 years and over |
0
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Recruitment
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Recruitment details |
The patients were recruited for the study from four university hospitals throughout Germany. The recruitment period was from December 2012 to May 2014. | ||||||||||||||
Pre-assignment
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Screening details |
Eligible patients were at least 18 years of age with confirmed diagnosis of livedoid vasculopathy and 40 points on the pain visual analogue scale. All patients were required to have a wash out phase of any previous treatment of at least 24 hours before study medication was administered. Patients with symptomatic bleeding disorders were excluded. | ||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
28 | ||||||||||||||
Number of subjects completed |
25 | ||||||||||||||
Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
violation of inclusion criteria: 2 | ||||||||||||||
Reason: Number of subjects |
lack of compliance: 1 | ||||||||||||||
Period 1
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Period 1 title |
Baseline
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
Arms
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Arm title
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Rivaroxaban - Baseline | ||||||||||||||
Arm description |
Patients at baseline (before rivaroxaban treatment was initiated). | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Xarelto 10 mg
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Investigational medicinal product code |
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Other name |
Rivaroxaban
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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 |
Patients were treated orally with rivaroxaban at an initial dose of 10 mg twice daily and it was reduced to 10 mg once daily when pain decreased. It was also possible to initiate the treatment with a dose of 10 mg once daily. In case of insufficient pain reduction, rivaroxaban was increased to 10 mg twice daily.
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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: 28 Patients were enrolled in the study and were allocated for treatment with rivaroxaban. But three of the patients dropped out before the baseline examination because of violation of inclusion criteria (2 patients) or lack of compliance (1 patient). Therefore, only 25 patients started the baseline period. |
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Period 2
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Period 2 title |
Week 4
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Is this the baseline period? |
No | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
Arms
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Arm title
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Rivaroxaban - Week 4 | ||||||||||||||
Arm description |
Patients who received rivaroxaban for 4 weeks. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Xarelto 10 mg
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Investigational medicinal product code |
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Other name |
Rivaroxaban
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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 |
Patients were treated orally with rivaroxaban at an initial dose of 10 mg twice daily and it was reduced to 10 mg once daily when pain decreased. It was also possible to initiate the treatment with a dose of 10 mg once daily. In case of insufficient pain reduction, rivaroxaban was increased to 10 mg twice daily.
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Period 3
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Period 3 title |
Week 8
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Is this the baseline period? |
No | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
Arms
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Arm title
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Rivaroxaban - Week 8 | ||||||||||||||
Arm description |
Patients who received rivaroxaban for 8 weeks. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Xarelto 10 mg
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Investigational medicinal product code |
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Other name |
Rivaroxaban
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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 |
Patients were treated orally with rivaroxaban at an initial dose of 10 mg twice daily and it was reduced to 10 mg once daily when pain decreased. It was also possible to initiate the treatment with a dose of 10 mg once daily. In case of insufficient pain reduction, rivaroxaban was increased to 10 mg twice daily.
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Period 4
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Period 4 title |
Week 12
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Is this the baseline period? |
No | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
Arms
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Arm title
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Rivaroxaban - Week 12 | ||||||||||||||
Arm description |
Patients who received rivaroxaban for 12 weeks. | ||||||||||||||
Arm type |
Experimental | ||||||||||||||
Investigational medicinal product name |
Xarelto 10 mg
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Investigational medicinal product code |
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Other name |
Rivaroxaban
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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 |
Patients were treated orally with rivaroxaban at an initial dose of 10 mg twice daily and it was reduced to 10 mg once daily when pain decreased. It was also possible to initiate the treatment with a dose of 10 mg once daily. In case of insufficient pain reduction, rivaroxaban was increased to 10 mg twice daily.
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Baseline characteristics reporting groups
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Reporting group title |
Baseline
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Rivaroxaban - Baseline
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Reporting group description |
Patients at baseline (before rivaroxaban treatment was initiated). | ||
Reporting group title |
Rivaroxaban - Week 4
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Reporting group description |
Patients who received rivaroxaban for 4 weeks. | ||
Reporting group title |
Rivaroxaban - Week 8
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Reporting group description |
Patients who received rivaroxaban for 8 weeks. | ||
Reporting group title |
Rivaroxaban - Week 12
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Reporting group description |
Patients who received rivaroxaban for 12 weeks. | ||
Subject analysis set title |
Enoxaparin - Baseline to Week 12
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients who reached the end of the study (week 12) and needed backup treatment with enoxaparin.
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End point title |
change in local pain between baseline and week 12 | ||||||||||||
End point description |
The primary endpoint is the change in local pain measured on a visual analogue scale (VAS) between baseline and week 12.
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End point type |
Primary
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End point timeframe |
baseline and week 12
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Notes [1] - Endpoint could be assessed only for 20 patients, because 5 patients had dropped out before week 12. [2] - Endpoint could be assessed only for 20 patients, because 5 patients had dropped out before week 12. |
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Statistical analysis title |
primary statistical analysis | ||||||||||||
Statistical analysis description |
The primary analysis was performed with a significance level of α = 0.05. The null hypothesis was tested with a two-sided Wilcoxon test for paired data. It was conducted according to the ITT principle and is considered confirmatory. Therapeutic effectiveness was considered clinically relevant with a mean effect size in the primary endpoint of at least Δ/σ=0.7. A minimum sample size of 20 evaluable patients was necessary to demonstrate a significant therapeutic effect with a power of 80%.
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Comparison groups |
Rivaroxaban - Baseline v Rivaroxaban - Week 12
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Number of subjects included in analysis |
40
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
2-sided exact Wilcoxon test | ||||||||||||
Parameter type |
Median difference (net) | ||||||||||||
Point estimate |
62.5
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
41.89 | ||||||||||||
upper limit |
68.81 |
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End point title |
change in local pain between baseline and week 4 | ||||||||||||
End point description |
The secondary endpoint is the change in local pain measured on a visual analogue scale (VAS) between baseline and week 4.
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End point type |
Secondary
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End point timeframe |
baseline and week 4
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Notes [3] - Endpoint could be assessed only for 21 patients, because 4 patients had dropped out before week 4. [4] - Endpoint could be assessed only for 21 patients, because 4 patients had dropped out before week 4. |
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Statistical analysis title |
secondary statistical analysis | ||||||||||||
Statistical analysis description |
Secondary endpoints were analyzed partly descriptively. In case of inductive analyses, two-sided Wilcoxon test for paired data were used and data were analyzed according to the intention-to-treat principle. These analyses are considered exploratory and are interpreted accordingly.
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Comparison groups |
Rivaroxaban - Baseline v Rivaroxaban - Week 4
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Number of subjects included in analysis |
42
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
2-sided exact Wilcoxon test | ||||||||||||
Confidence interval |
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End point title |
change in local pain between baseline and week 8 | ||||||||||||
End point description |
The secondary endpoint is the change in local pain measured on a visual analogue scale (VAS) between baseline and week 8.
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End point type |
Secondary
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End point timeframe |
baseline and week 8
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Notes [5] - Endpoint could be assessed only for 20 patients, because 5 patients had dropped out before week 8. [6] - Endpoint could be assessed only for 20 patients, because 5 patients had dropped out before week 8. |
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Statistical analysis title |
secondary statistical analysis | ||||||||||||
Statistical analysis description |
Secondary endpoints were analyzed partly descriptively. In case of inductive analyses, two-sided Wilcoxon test for paired data were used and data were analyzed according to the intention-to-treat principle. These analyses are considered exploratory and are interpreted accordingly.
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Comparison groups |
Rivaroxaban - Baseline v Rivaroxaban - Week 8
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Number of subjects included in analysis |
40
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 | ||||||||||||
Method |
2-sided exact Wilcoxon test | ||||||||||||
Confidence interval |
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End point title |
change in quality of life between baseline and week 4 | ||||||||||||
End point description |
The secondary endpoint is the change in quality of life measured with a Dermatology Life Quality Index (DLQI) questionnaire between baseline and week 4.
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End point type |
Secondary
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End point timeframe |
baseline and week 4
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Notes [7] - Endpoint could be assessed only for 21 patients, because 4 patients had dropped out before week 4. [8] - Endpoint could be assessed only for 21 patients, because 4 patients had dropped out before week 4. |
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Statistical analysis title |
secondary statistical analysis | ||||||||||||
Statistical analysis description |
Secondary endpoints were analyzed partly descriptively. In case of inductive analyses, two-sided Wilcoxon test for paired data were used and data were analyzed according to the intention-to-treat principle. These analyses are considered exploratory and are interpreted accordingly.
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Comparison groups |
Rivaroxaban - Baseline v Rivaroxaban - Week 4
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Number of subjects included in analysis |
42
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.005 | ||||||||||||
Method |
2-sided exact Wilcoxon test | ||||||||||||
Confidence interval |
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End point title |
change in quality of life between baseline and week 8 | ||||||||||||
End point description |
The secondary endpoint is the change in quality of life measured with a Dermatology Life Quality Index (DLQI) questionnaire between baseline and week 8.
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End point type |
Secondary
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End point timeframe |
baseline and week 8
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Notes [9] - Endpoint could be assessed only for 20 patients, because 5 patients had dropped out before week 8. [10] - Endpoint could be assessed only for 20 patients, because 5 patients had dropped out before week 8. |
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Statistical analysis title |
secondary statistical analysis | ||||||||||||
Statistical analysis description |
Secondary endpoints were analyzed partly descriptively. In case of inductive analyses, two-sided Wilcoxon test for paired data were used and data were analyzed according to the intention-to-treat principle. These analyses are considered exploratory and are interpreted accordingly.
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Comparison groups |
Rivaroxaban - Baseline v Rivaroxaban - Week 8
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Number of subjects included in analysis |
40
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.002 | ||||||||||||
Method |
2-sided exact Wilcoxon test | ||||||||||||
Confidence interval |
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End point title |
change in quality of life between baseline and week 12 | ||||||||||||
End point description |
The secondary endpoint is the change in quality of life measured with a Dermatology Life Quality Index (DLQI) questionnaire between baseline and week 12.
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End point type |
Secondary
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End point timeframe |
baseline and week 12
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Notes [11] - Endpoint could be assessed only for 20 patients, because 5 patients had dropped out before week 12. [12] - Endpoint could be assessed only for 20 patients, because 5 patients had dropped out before week 12. |
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Statistical analysis title |
secondary statistical analysis | ||||||||||||
Statistical analysis description |
Secondary endpoints were analyzed partly descriptively. In case of inductive analyses, two-sided Wilcoxon test for paired data were used and data were analyzed according to the intention-to-treat principle. These analyses are considered exploratory and are interpreted accordingly.
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Comparison groups |
Rivaroxaban - Baseline v Rivaroxaban - Week 12
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Number of subjects included in analysis |
40
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
2-sided exact Wilcoxon test | ||||||||||||
Confidence interval |
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End point title |
Consumption of rescue medication - use of injections | ||||||||
End point description |
The secondary endpoint is the use of enoxaparin injections from baseline to week 12.
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End point type |
Secondary
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End point timeframe |
From baseline to week 12.
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No statistical analyses for this end point |
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End point title |
Consumption of rescue medication - duration of administration | ||||||||
End point description |
The secondary endpoint is the duration of enoxaparin administration from baseline to week 12.
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End point type |
Secondary
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End point timeframe |
From baseline to week 12.
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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 enrollment in the study to week 12 (reported adverse events were followed up after week 12).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
17.0
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Reporting groups
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Reporting group title |
Safety group
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Reporting group description |
Adverse Events were evaluated descriptively according to the as-treated principle. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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? Yes | |||
Date |
Amendment |
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20 Sep 2013 |
The protocol was amended to add and modify some exclusion criteria and to modify the administration of the study medication in terms of initial dosing. At the beginning of the trial, the treatment was initiated with 10 mg rivaroxaban orally twice daily and was reduced to 10 mg orally once daily when pain decreased. After the amendment, the treatment was initiated with 10 mg rivaroxaban orally once daily and only in case of insufficient pain reduction, rivaroxaban was increased to 10 mg twice daily.
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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. | |||
None reported | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/26853646 |