PADOASU: In Vitro Diagnostic Test for DOAC in Urine
Study Details
Study Description
Brief Summary
This trial is conducted to assess the performance and handling of the in vitro diagnostic (IVD) device for oral direct factor Xa and thrombin inhibitors from urine samples of patients on treatment with direct oral anticoagulants Apixaban, Edoxaban, Rivaroxaban, and Dabigatran (DOAC) in an actual point-of-care (POCT) setting in comparison to results obtained by liquid chromatography tandem mass spectrometry (LC-MS/MS) from urine samples.
This trial is conducted to assess the performance and handling of the IVD for oral direct factor Xa and thrombin inhibitors from urine samples of patients on treatment with DOACs in an actual point-of-care setting in comparison to results obtained by liquid chromatography tandem mass spectrometry (LC-MS/MS) from urine samples.
"publication Thromb Haemost. 2019 Nov 8. doi: 10.1055/s-0039-1700545. [Epub ahead of print]"
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Detailed Description
This prospective, open-label, controlled, not randomized Performance Assessment will be conducted as a multicenter Performance Assessment in Germany.
The trial investigates the sensitivity and specificity of a POCT for DOAC, i.e., the rate of correct positive, false positive, correct negative and false negative results in the point-of-care setting. The IVD is a test to determine absence or presence of DOAC in urine - Test A tests for oral direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban), Test B for oral thrombin inhibitors (dabigatran).
Two groups of patients will be included:
-
Test group A: Patients under therapy with oral direct factor Xa inhibitor (rivaroxaban, apixaban, and edoxaban) (n=440)
-
Test group B: Patients under therapy with oral thrombin inhibitors (dabigatran) (n=440) No control group of patients not treated with a DOAC is required, as patients take either oral direct factor Xa inhibitors (Test group A) or oral thrombin inhibitors (Test group B), never both. Thus, patients in Test group A are negative for oral thrombin inhibitors and can serve as negative control for Test group B, and vice versa.
The point-of-care test (POCT) is a color-indicator diagnostic medical urine dipstick test for assessing the presence of oral direct factor Xa inhibitor (rivaroxaban, apixaban, and edoxaban) and thrombin inhibitors (dabigatran). The principle of the diagnostic test is based on the development of different colors on the indicator part of the dipstick in the presence or absence of oral direct factor Xa (rivaroxaban, apixaban, and edoxaban) and thrombin inhibitors (dabigatran). The colors for the test were chosen so that they could easily be read by the naked eye, with little possibility of incorrect identification of colors. The results for presence or absence will be compared with the concentration of DOAC analyzed by LC-MS/MS.
Two groups of medications (thrombin inhibitors, factor Xa inhibitors) will be tested with the IVD and test results compared to bioanalytical results in urine.
The objective of the investigation is to show that the proportion of false negative and false positive tests with the IVD is below 5%.
The required sample size to show that the assumed rate of 2.5% false-negative/false-positive tests is statistically significant lower than 5% would require 384 patients per each test group, with α=0.05 and β=0.20 (80% power). Accounting for a potential drop-out rate of 12%, a sample size of n=440 patients per test group was considered adequate to demonstrate adequate performance of the IVD. This sample size has been assessed with the SAS procedure PROC POWER (SAS Institute Inc., Cary, NC, USA, release 9.3) using the ONESAMPLEFREQ statement under the assumption that the test will be conducted as a 1-sided test with a null proportion of 0.05.
For each diagnostic test the proportions of false negative and false positive results will be assessed together with confidence intervals. The urine concentration serves as a gold standard. Furthermore, McNemar tests will be conducted in order to compare the sensitivity, the specificity, accuracy, negative predictive value, positive predictive value and likelihood probability of the two different medications. Kappa coefficients will be calculated in order to quantify the strength of agreement between two diagnostic test methods.
As the study design is not randomized the two groups will be compared according to biographic data (i.e. age, gender, concentration in urine) by common statistical tests (Chi2 test, t-test) in order to investigate their equality. In the case of differences between groups statistical adjustment will be done (i.e. propensity score) in order to avoid the influence of a bias.
The Performance Assessment will be conducted at the patient's family doctor or medical practice/outpatient care unit (referred to as "investigational site" in the following).
The Performance Assessment will consist of a single visit, which is performed during a routine visit at the investigational site.
The Performance Assessment starts with first patient signing informed consent (FPFV) and ends with the last patient providing the last sample (last patient last visit, LPLV).
"publication Thromb Haemost. 2019 Nov 8. doi: 10.1055/s-0039-1700545. [Epub ahead of print]"
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Factor Xa inhibitor Patients on treatment with Apixaban, Edoxaban or Rivaroxaban are included into the evaluation study at the outpatient care unit. Patients receive treatment for a specific clinical indication such as non-valvular atrial fibrillation or venous thromboembolism since one week or longer. During the study visit DOAC Dipstick test and liquid-chromatography mass-specrotmery are performed to identify absence or presence of Factor Xa inhibitor in urine. "publication Thromb Haemost. 2019 Nov 8. doi: 10.1055/s-0039-1700545. [Epub ahead of print]" |
Diagnostic Test: DOAC Dipstick
Patients collect a sample of urine for analysis.
"publication Thromb Haemost. 2019 Nov 8. doi: 10.1055/s-0039-1700545. [Epub ahead of print]"
Other Names:
|
| Thrombin inhibitor Patients on treatment with Dabigatran are included included into the evaluation study at the outpatient care unit. Patients receive treatment for a specific clinical indication such as non-valvular atrial fibrillation or venous thromboembolism since one week or longer. During the study visit DOAC Dipstick test and liquid-chromatography mass-specrotmery are performed to identify absence or presence of Thrombin inhibitor in urine. "publication Thromb Haemost. 2019 Nov 8. doi: 10.1055/s-0039-1700545. [Epub ahead of print]" |
Diagnostic Test: DOAC Dipstick
Patients collect a sample of urine for analysis.
"publication Thromb Haemost. 2019 Nov 8. doi: 10.1055/s-0039-1700545. [Epub ahead of print]"
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Accuracy of Factor Xa and Thrombin Inhibitors Pads of DOAC Dipstick From Urine Samples [during urine collection and bioanalytical quantification, any time between August 2018 and April 2019]
Liquid chromatography mass spectrometry versus DOAC Dipstick, qualitative analysis of results
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Fully signed and dated written informed consent
-
Age >18 years
-
Patient is either under therapy with rivaroxaban, apixaban, and edoxaban or dabigatran for at least 1 week
Exclusion Criteria:
-
Patients not able to provide urine samples.
-
Patients not able to understand the informed consent or severe mentally disabled.
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Patients in the end-stage of a severe disease.
"publication Thromb Haemost. 2019 Nov 8. doi: 10.1055/s-0039-1700545. [Epub ahead of print]"
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Universitätsherzzentrum Bad Krozingen, Klinik für Kardiologie und Angiologie II | Bad Krozingen | Germany | 79189 | |
| 2 | Herz- und Diabeteszentrum NRW, Klinik für Kardiologie | Bad Oeynhausen | Germany | 32545 | |
| 3 | Vivantes Klinikum im Friedrichshain | Berlin | Germany | 10249 | |
| 4 | Gerinnungszentrum Sucker | Berlin | Germany | 10789 | |
| 5 | Vivantes Klinikum Neukölln | Berlin | Germany | 12351 | |
| 6 | Klinikum Coburg GmbH, II. Medizinische Klinik | Coburg | Germany | 96450 | |
| 7 | Klinikum Darmstadt - Gefäßzentrum | Darmstadt | Germany | 64283 | |
| 8 | Praxis Innere Medizin, Kardiologie und Angiologie | Dessau | Germany | 06846 | |
| 9 | Städtisches Klinikum Dresden, II. Medizinische Klinik | Dresden | Germany | 01067 | |
| 10 | Medizinische Fakultät Carl Gustav Carus, Medizinische Klinik und Poliklinik I | Dresden | Germany | 01307 | |
| 11 | Cardioangiologisches Centrum Bethanien | Frankfurt | Germany | 60389 | |
| 12 | Klinik für Kardiologie und Angiologie I | Freiburg | Germany | 79106 | |
| 13 | Universitätsklinikum Hamburg-Eppendorf, II. Medizinische Klinik und Poliklinik | Hamburg | Germany | 20246 | |
| 14 | Kliniken Landkreis Heidenheim | Heidenheim | Germany | 89522 | |
| 15 | Krankenhaus der Augustinerinnen gGmbH, Klinik für Kardiologie und internistische Intensivmedizin | Köln | Germany | 50678 | |
| 16 | Zentrum für Blutgerinnungsstörungen, MVZ Labor Dr. Reising-Ackermann und Kollegen | Leipzig | Germany | 04289 | |
| 17 | Zentrum für Praevention und Rehabilitation | Siegen | Germany | 57072 | |
| 18 | Die Parkkardiologie | Stahnsdorf | Germany | 14532 |
Sponsors and Collaborators
- Doasense GmbH
- Clinical Research Services, Mannheim, Germany
- Institute Medical Statistics, Medical Faculty Mannheim
- Medical Care Center Dr. Limbach and Colleagues, Heidelberg, Germany
Investigators
- Principal Investigator: Job Harenberg, Professor, Pneumonologische Schwerpunktpraxis Heidelberg, Privatpraxis Harenberg
Study Documents (Full-Text)
More Information
Additional Information:
Publications
- Du S, Weiss C, Christina G, Krämer S, Wehling M, Krämer R, Harenberg J. Determination of dabigatran in plasma, serum, and urine samples: comparison of six methods. Clin Chem Lab Med. 2015 Jul;53(8):1237-47. doi: 10.1515/cclm-2014-0991.
- Harenberg J, Du S, Krämer S, Weiss C, Krämer R, Wehling M. Patients' serum and urine as easily accessible samples for the measurement of non-vitamin K antagonist oral anticoagulants. Semin Thromb Hemost. 2015 Mar;41(2):228-36. doi: 10.1055/s-0035-1544158. Epub 2015 Feb 15. Review.
- Harenberg J, Du S, Wehling M, Zolfaghari S, Weiss C, Krämer R, Walenga J. Measurement of dabigatran, rivaroxaban and apixaban in samples of plasma, serum and urine, under real life conditions. An international study. Clin Chem Lab Med. 2016 Feb;54(2):275-83. doi: 10.1515/cclm-2015-0389.
- Harenberg J, Schreiner R, Hetjens S, Weiss C. Detecting Anti-IIa and Anti-Xa Direct Oral Anticoagulant (DOAC) Agents in Urine using a DOAC Dipstick. Semin Thromb Hemost. 2019 Apr;45(3):275-284. doi: 10.1055/s-0038-1668098. Epub 2018 Aug 22.
- DOA-CS-002
Study Results
Participant Flow
| Recruitment Details | Start of study: 18.08.2018 End of study: 10.04.2019 18 centres |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Factor Xa Inhibitor | Thrombin Inhibitor |
|---|---|---|
| Arm/Group Description | The aim was to include 450 patients on stable treatment with apixaban, edoxaban and rivaroxaban | The aim was to include 450 patients on stable treatment with dabigatran |
| Period Title: Overall Study | ||
| STARTED | 467 | 444 |
| COMPLETED | 451 | 429 |
| NOT COMPLETED | 16 | 15 |
Baseline Characteristics
| Arm/Group Title | Factor Xa Inhibitor | Thrombin Inhibitor | Total |
|---|---|---|---|
| Arm/Group Description | Patients on therapy with apixaban, edoxaban and rivaroxaban for at least 7 days | Patients on therapy with dabigatran for at least 7 days | Total of all reporting groups |
| Overall Participants | 451 | 429 | 880 |
| Age (Count of Participants) | |||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
320
71%
|
312
72.7%
|
632
71.8%
|
| >=65 years |
131
29%
|
117
27.3%
|
248
28.2%
|
| Age (years) [Mean (Full Range) ] | |||
| Mean (Full Range) [years] |
67
|
70
|
68
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
201
44.6%
|
138
32.2%
|
339
38.5%
|
| Male |
250
55.4%
|
291
67.8%
|
541
61.5%
|
| Race/Ethnicity, Customized (participants) [Number] | |||
| Number [participants] |
451
100%
|
429
100%
|
880
100%
|
| Region of Enrollment (participants) [Number] | |||
| Germany |
451
100%
|
429
100%
|
880
100%
|
Outcome Measures
| Title | Accuracy of Factor Xa and Thrombin Inhibitors Pads of DOAC Dipstick From Urine Samples |
|---|---|
| Description | Liquid chromatography mass spectrometry versus DOAC Dipstick, qualitative analysis of results |
| Time Frame | during urine collection and bioanalytical quantification, any time between August 2018 and April 2019 |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Factor Xa Inhibitor | Thrombin Inhibitor |
|---|---|---|
| Arm/Group Description | Patients on treatment with apixaban, edoxaban, rivaroxaban | Patients treated with dabigatran |
| Measure Participants | 451 | 429 |
| Mean (95% Confidence Interval) [percentage of correct responses] |
0.973
|
0.993
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Factor Xa Inhibitor, Thrombin Inhibitor |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Non-Inferiority | |
| Comments | non-inferiority was chosen | |
| Statistical Test of Hypothesis | p-Value | <0.05 |
| Comments | ||
| Method | Chi-squared | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Mean Difference (Final Values) |
| Estimated Value | 100 | |
| Confidence Interval |
(2-Sided) 95% 90 to 100 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Other Statistical Analysis | Fisher's exact test | |
Adverse Events
| Time Frame | 2 hours | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Adverse Events were not routinely assessed | |||
| Arm/Group Title | Factor Xa Inhibitor | Thrombin Inhibitor | ||
| Arm/Group Description | Patients on treatment with apxiban, edoxaban and rivaroxaban | Patients on treatment with dabigatran | ||
All Cause Mortality |
||||
| Factor Xa Inhibitor | Thrombin Inhibitor | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/0 (NaN) | 0/0 (NaN) | ||
Serious Adverse Events |
||||
| Factor Xa Inhibitor | Thrombin Inhibitor | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/0 (NaN) | 0/0 (NaN) | ||
Other (Not Including Serious) Adverse Events |
||||
| Factor Xa Inhibitor | Thrombin Inhibitor | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/0 (NaN) | 0/0 (NaN) | ||
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
| Name/Title | Harenberg, Job Prof Dr. |
|---|---|
| Organization | DOASENSE GmbH |
| Phone | +496221825 ext 9785 |
| j.harenberg@doasense.de |
- DOA-CS-002