Clinical Trial Results:
Effect of anticoagulation therapy on clinical outcomes in COVID-19 (COVID-PREVENT)
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Summary
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EudraCT number |
2020-002282-33 |
Trial protocol |
DE |
Global end of trial date |
06 Oct 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
08 Jun 2023
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First version publication date |
08 Jun 2023
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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 |
COVID-PREVENT
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04416048 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Charité - University Hospital of Berlin
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Sponsor organisation address |
Charitéplatz 1, Berlin, Germany, 10117
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Public contact |
Med. Klinik für Kardiologie, Charité - Universitätsmedizin Berlin, +49 30450513702, ulf.landmesser@charite.de
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Scientific contact |
Prof. Dr. Ulf Landmesser , Charité - CBF, +49 30450513702, ulf.landmesser@charite.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 |
31 May 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
17 Jun 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Oct 2021
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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 primary objective is to assess the effect of rivaroxaban compared with standard of care (SOC) with the use of prophylactic low molecular weight heparin (LMWH) or unfractionated heparin (UFH) on D-dimer as a clinical marker for the clinical outcome at day 7 post randomization adjusted for baseline measurement in patients with moderate to severe COVID-19.
The co-primary objective is to evaluate the impact of rivaroxaban compared with standard of care (SOC) with the use of prophylactic low molecular weight heparin (LMWH) or unfractionated heparin (UFH) on a seven-category ordinal scale recommended by the WHO as a measure of clinical benefit at day 7 post randomization adjusted for baseline score in patients with moderate to severe COVID-19.
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Protection of trial subjects |
Non applicable
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
30 Nov 2020
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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: 111
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Worldwide total number of subjects |
111
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EEA total number of subjects |
111
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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) |
63
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From 65 to 84 years |
42
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85 years and over |
6
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Recruitment
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Recruitment details |
The study was conducted at 22 study centers in Germany. Adults with moderate to severe COVID-19 and a high thrombotic risk were included in the study. Patients with an indication for a chronic anticoagulation or with a high bleeding risk were excluded from the study. | |||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 117 patients were screened, 6 were screening failure, so that at the end 111 patients were enrolled and randomized. | |||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Treatment (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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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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Rivaroxaban group | |||||||||||||||||||||||||||||||||
Arm description |
Subjects receivedrivaroxaban 20 mg (15 mg for subjects with an eGFR ≥30 mL/min/1.73m2 and <50 mL/min/1.73m2) once daily (OD) for at least 7 days or until hospital discharge, whichever occurred later. After this full-anticoagulation phase, the patients received rivaroxaban 10mg OD for 28 days. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Rivaroxaban
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Investigational medicinal product code |
366789-02-8
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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 |
Treatment with Rivaroxaban 20 mg (15 mg for subjects with an eGFR ≥30 mL/min/1.73m2 and <50 mL/min/1.73m2) once daily (OD) for at least 7 days was given. In case of hospitalization for more than 7 days, the therapeutic treatment with rivaroxaban was continued for the duration of the hospital stay until discharge.
After at least 7 days of therapeutic treatment with rivaroxaban or after hospital discharge, the daily dosage was reduced to 10 mg OD for 28 days.
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Arm title
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Standard of care | |||||||||||||||||||||||||||||||||
Arm description |
The patients in this group were treated with prophylactic low molecular weight heparin (LMWH) or unfractioned heparin (UFH) until day 7 post randomization or until discharge, whichever occurred later | |||||||||||||||||||||||||||||||||
Arm type |
control group | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Unfractioned heparin of low molecular weight heparin
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Investigational medicinal product code |
SUB12369MIG
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Other name |
TINZAPARIN SODIUM
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Pharmaceutical forms |
Anticoagulant and preservative solution for blood
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Routes of administration |
Intravenous use, Subcutaneous use
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Dosage and administration details |
The patients in this group were treated with prophylactic low molecular weight heparin (LMWH) or unfractioned heparin (UFH) until day 7 post randomization or until discharge, whichever occurred later.
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Baseline characteristics reporting groups
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Reporting group title |
Rivaroxaban group
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Reporting group description |
Subjects receivedrivaroxaban 20 mg (15 mg for subjects with an eGFR ≥30 mL/min/1.73m2 and <50 mL/min/1.73m2) once daily (OD) for at least 7 days or until hospital discharge, whichever occurred later. After this full-anticoagulation phase, the patients received rivaroxaban 10mg OD for 28 days. | ||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Standard of care
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Reporting group description |
The patients in this group were treated with prophylactic low molecular weight heparin (LMWH) or unfractioned heparin (UFH) until day 7 post randomization or until discharge, whichever occurred later | ||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Rivaroxaban group
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Reporting group description |
Subjects receivedrivaroxaban 20 mg (15 mg for subjects with an eGFR ≥30 mL/min/1.73m2 and <50 mL/min/1.73m2) once daily (OD) for at least 7 days or until hospital discharge, whichever occurred later. After this full-anticoagulation phase, the patients received rivaroxaban 10mg OD for 28 days. | ||
Reporting group title |
Standard of care
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Reporting group description |
The patients in this group were treated with prophylactic low molecular weight heparin (LMWH) or unfractioned heparin (UFH) until day 7 post randomization or until discharge, whichever occurred later | ||
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End point title |
D-dimer at day 7 post randomization | |||||||||||||||
End point description |
The primary objective is to assess the effect of rivaroxaban compared with standard of care (SOC) with the use of prophylactic low molecular weight heparin (LMWH) or unfractionated heparin (UFH) on D-dimer as a clinical marker for the clinical outcome at day 7 post randomization adjusted for baseline measurement in patients with moderate to severe COVID-19.
The logarithmic D-dimer measurements (using the natural logarithm) was analyzed by an analysis of covariance (ANCOVA). The model included treatment group and stratification variables of the randomization as factors and the logarithmic baseline D-dimer measurement as covariate. Least squares means for D-dimer at day 7 in the two treatment groups is presented with 95% confidence intervals as well as the difference between the treatment groups at day 7 with 95% confidence interval and p-value testing the null hypothesis of no treatment difference, i.e. a mean difference (on the logarithmic scale) of 0.
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End point type |
Primary
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End point timeframe |
Measurement of D-dimer at day 7 post randomization
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Statistical analysis title |
treatment effect (log-scale) [log(mg/L)] | |||||||||||||||
Comparison groups |
Rivaroxaban group v Standard of care
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Number of subjects included in analysis |
82
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | |||||||||||||||
P-value |
= 0 | |||||||||||||||
Method |
ANCOVA | |||||||||||||||
Parameter type |
mean difference log scale | |||||||||||||||
Confidence interval |
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End point title |
Seven-category ordinal scale at day 7 post randomization | |||||||||||||||||||||||||||
End point description |
Co-primary efficacy outcome:
Regarding the co-primary efficacy outcome, a 7-day course of rivaroxaban at a therapeutic dose of 20 mg daily compared to heparin at a prophylactic dose improved in trend the 7-category ordinal scale as a measure for the clinical outcome.
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End point type |
Primary
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End point timeframe |
7 days post randomization
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Statistical analysis title |
Co-primary efficacy outcome | |||||||||||||||||||||||||||
Comparison groups |
Rivaroxaban group v Standard of care
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Number of subjects included in analysis |
108
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||||||||||||||||||||
P-value |
= 1 | |||||||||||||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | |||||||||||||||||||||||||||
Parameter type |
rank sum test | |||||||||||||||||||||||||||
Confidence interval |
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End point title |
Secondary efficacy outcome | |||||||||||||||||||||||||||
End point description |
Time to first event of either of:
• Venous thromboembolism (deep venous thrombosis and/or fatal or non-fatal pulmonary embolism)
• Arterial thromboembolism
• New myocardial infarction
• Non-hemorrhagic stroke
• All-cause death
• Progression to intubation and invasive ventilation
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End point type |
Secondary
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End point timeframe |
Until day 35 post randomization
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End point title |
Safety outcomes | |||||||||||||||||||||
End point description |
The primary safety outcome occurred in 1 of 111 patients (0.9%) of the whole study population. This patient was assigned to the rivaroxaban group and had a non-fatal major bleeding according to the ISTH criteria.
The secondary efficacy outcome defined as non-major clinical relevant bleeding occurred in two patients in the rivaroxaban-group and in three patients in the SOC-group.
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End point type |
Other pre-specified
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End point timeframe |
overall study
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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 |
Serious adverse events within 24 hours, as well as adverse events that were secondary efficacy endpoints or safety endpoints. Non-serious adverse events were collected and reported in each subsequent visit.
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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 |
25
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Reporting groups
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Reporting group title |
Rivaroxaban
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Reporting group description |
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Reporting group title |
SOC-Standard or care
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 1.5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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20 Aug 2021 |
The initial planned sample size based on statistical calculations was 400 patients. Due to decreasing COVID incidence rates, it became very likely not to be able to recruit the planned patient number within
a reasonable time frame to contribute with the results to the treatment of patients suffering from COVID.
The main changes were:
- Primary efficacy endpoints and its corresponding statistical analysis
- Secondary efficacy endpoints and its corresponding statistical analysis
- Sample size determination
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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. | |||||||
| The biggest limitation of the study was the small number of patients included. Due to the low recruitment, it wasn’t possible to test the initial primary hypothesis with the sufficient statistical power. For this reason, the outcomes in the protocol | |||||||
