Clinical Trial Results:
An open-label, international, multicenter, interventional study exploring the efficacy of once-daily oral rivaroxaban (BAY 59 7939) for the treatment of left atrial/left atrial appendage thrombus in subjects with nonvalvular atrial fibrillation or atrial flutter
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Summary
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EudraCT number |
2012-001062-15 |
Trial protocol |
DE BG PL |
Global end of trial date |
25 Dec 2014
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Results information
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Results version number |
v3(current) |
This version publication date |
17 Feb 2019
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First version publication date |
15 Jul 2016
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Other versions |
v1 , v2 |
Version creation reason |
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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 |
BAY59-7939/16320
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01839357 | ||
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 |
25 Dec 2014
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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 |
25 Dec 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 primary objective of the study was to explore the effect of rivaroxaban on the complete resolution of left atrial (LA)/left atrial appendage (LAA) thrombi at the end-of-treatment visit (after 6 weeks of treatment) in subjects with nonvalvular atrial fibrillation (AF) or atrial flutter who had LA/LAA thrombus confirmed by transesophageal echocardiogram (TEE).
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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 the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent explained to all 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 |
12 Aug 2013
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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 |
Bulgaria: 5
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Country: Number of subjects enrolled |
Poland: 29
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Country: Number of subjects enrolled |
Turkey: 8
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Country: Number of subjects enrolled |
Ukraine: 15
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Country: Number of subjects enrolled |
France: 1
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Country: Number of subjects enrolled |
Germany: 2
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Worldwide total number of subjects |
60
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EEA total number of subjects |
37
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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) |
23
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From 65 to 84 years |
37
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85 years and over |
0
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Recruitment
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Recruitment details |
Study was conducted in 17 study centers in 7 countries worldwide, from 12 August 2013 (first subject first visit) to 25 December 2014 (last subject last visit). | ||||||||||||||
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Pre-assignment
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Screening details |
Overall, 61 subjects were screened and 60 of these subjects were enrolled. The 1 subject enrolled at the site in Russia was the screen failure. Of the 60 subjects enrolled in the study, 57 were from Eastern Europe and 3 were from Western Europe. | ||||||||||||||
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Period 1
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Period 1 title |
Overall Trial (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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Arm title
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Rivaroxaban (Xarelto, BAY59-7939) | ||||||||||||||
Arm description |
Subjects received rivaroxaban 20 milligram (mg) orally once daily (od) for 6 weeks. Subjects with moderate to severe renal impairment (ie, Creatinine Clearence [CrCl] of 15 to 49 millilitre/minute [mL/min], inclusive) at screening received an adjusted dose of 15 mg orally od. Subjects were instructed to take rivaroxaban with food. The duration of study drug treatment was 6 (+2) weeks. A time window (maximum 2 weeks) were kept for the investigators to schedule the end-of-treatment TEE. | ||||||||||||||
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 |
Tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received 20 mg of rivaroxaban tablet orally od for 6 weeks.
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Baseline characteristics reporting groups
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Reporting group title |
Rivaroxaban (Xarelto, BAY59-7939)
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Reporting group description |
Subjects received rivaroxaban 20 milligram (mg) orally once daily (od) for 6 weeks. Subjects with moderate to severe renal impairment (ie, Creatinine Clearence [CrCl] of 15 to 49 millilitre/minute [mL/min], inclusive) at screening received an adjusted dose of 15 mg orally od. Subjects were instructed to take rivaroxaban with food. The duration of study drug treatment was 6 (+2) weeks. A time window (maximum 2 weeks) were kept for the investigators to schedule the end-of-treatment TEE. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Rivaroxaban (Xarelto, BAY59-7939)
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Reporting group description |
Subjects received rivaroxaban 20 milligram (mg) orally once daily (od) for 6 weeks. Subjects with moderate to severe renal impairment (ie, Creatinine Clearence [CrCl] of 15 to 49 millilitre/minute [mL/min], inclusive) at screening received an adjusted dose of 15 mg orally od. Subjects were instructed to take rivaroxaban with food. The duration of study drug treatment was 6 (+2) weeks. A time window (maximum 2 weeks) were kept for the investigators to schedule the end-of-treatment TEE. | ||
Subject analysis set title |
Intent-to-treat (ITT) population
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All subjects who successfully completed the screening phase and entered the treatment phase (whether or not they were actually treated).
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Subject analysis set title |
Modified ITT (mITT) population
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
All subjects with LA/ LAA thrombus at baseline who had an evaluable end-of-treatment TEE according to the adjudication committee.
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Subject analysis set title |
Per protocol set (PPS)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
All subjects from the mITT population without major protocol deviations.
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Subject analysis set title |
Safety analysis (SAF)
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects in the ITT analysis population who received at least 1 dose of study medication during the treatment period.
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End point title |
Percentage of Subjects With Complete Resolution of Left Atrial or Left Atrial Appendage (LA/LAA) Thrombus at the end of Treatment [1] | ||||||||||||
End point description |
Complete resolution of LA/LAA thrombus is adjudicated and confirmed by Study Outcome Committee. Complete resolution is characterized as the subject is completely thrombus-free in his/her left atrium confirmed on transesophageal echocardiography.
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End point type |
Primary
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End point timeframe |
Up to 8 weeks
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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: EudraCT database does auto-addition of number of subjects analysed while reporting an explorative analysis of two or more treatment groups. Due to this format constraint, charts have been uploaded with the accurate details of statistical analyses for this endpoint. Please find the statistical analyses in the attachment below. |
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Attachments |
16320_ Statistical Analyses_Primary_ Thrombus Reso |
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| Notes [2] - mITT population |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Categories of Thrombus Outcome in Subjects: Resolved, Reduced, Unchanged, Enlarged or New | ||||||||||||||||||||
End point description |
Individual thrombi were evaluated (in increasing order of severity) as resolved, reduced, unchanged, or enlarged since baseline, or new as compared to baseline, and subjects were categorized accordingly. 1) Resolved: absence of thrombus. 2) Reduced: decrease more than 1 millimetre (mm) by diameter (D) compared to baseline (average diameter [AD] is less than (<)10) or decrease more than 2 mm by D compared to baseline (AD is 10-20 mm) or decrease more than 3 mm by D compared to baseline (AD is > 20). 3) Unchanged: within 1 mm by D difference compared to baseline (AD is <10) or within 2 mm by D difference compared to baseline (AD is 10-20) or within 3 mm by D difference compared to baseline (AD is >20). 4) Larger: increase more than 1 mm by D compared to baseline (AD is <10) or increase more than 2 mm by D compared to baseline (AD is 10-20) or increase more than 3 mm by D compared to baseline (AD is >20). 5) New: new thrombus present. ‘99999’ indicates that data were not calculated.
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End point type |
Secondary
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End point timeframe |
Up to 8 weeks
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| Notes [3] - mITT population |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Combined Categories of Thrombus Outcome in Subjects | ||||||||||||
End point description |
Combined thrombi were evaluated as Resolved/reduced and Unchanged/enlarged/new.
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End point type |
Secondary
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End point timeframe |
Up to 8 weeks
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| Notes [4] - mITT population |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Composite Number of Stroke and Non-central Nervous System (Non-CNS) Systemic Embolism Events | |||||||||
End point description |
Stroke and Non-CNS Embolism were adjudicated and confirmed by Study Outcome Committee . Stroke included hemorrhagic and ischemic infarction. Non-CNS systemic embolism included emboli in peripheral arterial of the upper and lower extremities, ocular and retinal (pulmonary embolism and myocardial ischemia were excluded from the category).
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End point type |
Secondary
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End point timeframe |
Approximately up to 10 weeks
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| No statistical analyses for this end point | ||||||||||
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End point title |
Number of all Bleeding Events | ||||||||||||||
End point description |
Bleeding was categorized as major and non-major bleeding. For major bleedings, the following characteristics were displayed according to the following hierarchy: fatal bleeding, non-fatal critical organ bleed, non-fatal noncritical organ bleeding (decrease in hemoglobin level of 2 grams per deciliter (g/dL) and/or transfusions >= 2 units). No major bleeding event was reported. The non-major bleeding events included two serious events (moderate ear hemorrhage and moderate epistaxis) and three nonserious bleeding events (mild gingival bleeding, mild gastrointestinal hemorrhage and mild petechiae).
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End point type |
Secondary
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End point timeframe |
Approximately up to 10 weeks
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| Notes [5] - 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 treatment until the follow-up visit occurred 30 (+- 3) days after the end-of-treatment visit.
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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 |
17.1
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Reporting groups
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Reporting group title |
Rivaroxaban (Xarelto, BAY59-7939)
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Reporting group description |
Subjects received rivaroxaban 20 milligram (mg) orally once daily (od) for 6 weeks. Subjects with moderate to severe renal impairment (ie, Creatinine Clearenve [CrCl] of 15 to 49 millilitre/minute [mL/min], inclusive) at screening received an adjusted dose of 15 mg orally od. Subjects were instructed to take rivaroxaban with food. The duration of study drug treatment is 6 (+2) weeks. A time window (maximum 2 weeks) were kept for the investigators to schedule the end-of-treatment transesophageal echocardiography (TEE) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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18 Jan 2013 |
The title page of the noninterventional study protocol in Section 14.6 was removed and the synopsis was replaced with the new synopsis. |
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26 Feb 2014 |
This amendment also helped to enroll subjects from Western European Union (EU) countries as the availability of vitamin K antagonist(s) [VKA]/non-vitamin K antagonist or new oral anticoagulant(s) VKA/non-VKA or new oral anticoagulant(s) [NOAC]-naive subjects with atrial fibrillation is limited. Other revisions with Amendment 3 included: 1.Changed the Sponsor’s medical expert, 2. Added information that specified inclusion criteria regarding prior VKA and NOAC treatment, 3. Added a Study Outcome Committee to apply protocol definitions and adjudicate and classify endpoints on TEE, 4. Deleted the time period of “1 year” from enrollment criteria, 5. Added “Active endocarditis” to cardiac-related exclusion criteria, 6. Clarified that all eligible subjects should receive the study drug within 24 hours after treatment assignment, 7. Clarified duration of treatment, 8. Modified the evaluation schedule to clarify timing of electrocardiogram (ECG), trans-esophageal echocardiography/echocardiogram (TEE), laboratory evaluations and baseline blood sample, 9. Changed the timing of Visit 1 (Screening) procedures from within “2” days to “3” days prior to the start of the study drug treatment, 10. Added baseline characteristics to determine subgroups, 11. Deleted text from Statistical and analytical plans to be consistent with the statistical analysis plan. |
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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. | |||
| Occurrence of "±” in relation with geometric coefficient of variation is auto-generated and cannot be deleted. Decimal places were automatically truncated if last decimal equals zero. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/25819852 |
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