In Vitro Diagnostic Test for DOAC in Urine

Study Overview
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Brief Summary
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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]

Detailed Description
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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]

Official Title
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Post Marketing Study of an in Vitro Diagnostic Test for Direct Oral Anticoagulants (Apixaban, Edoxaban, Rivaroxaban, Dabigatran) in Urine

Conditions
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Anticoagulant Therapy

Intervention / Treatment
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* Diagnostic Test: DOAC Dipstick


Participation Criteria
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Eligibility Criteria
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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. 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]

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Factor Xa inhibitor<br>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<br>* Patients collect a sample of urine for analysis. publication Thromb Haemost. 2019 Nov 8. doi: 10.1055/s-0039-1700545. [Epub ahead of print]<br>* Other names: test strip for urine analysispublication Thromb Haemost. 2019 Nov 8. doi: 10.1055/s-0039-1700545. [Epub ahead of print];|
| Thrombin inhibitor<br>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<br>* Patients collect a sample of urine for analysis. publication Thromb Haemost. 2019 Nov 8. doi: 10.1055/s-0039-1700545. [Epub ahead of print]<br>* Other names: test strip for urine analysispublication Thromb Haemost. 2019 Nov 8. doi: 10.1055/s-0039-1700545. [Epub ahead of print];|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Accuracy of Factor Xa and Thrombin Inhibitors Pads of DOAC Dipstick From Urine Samples | Liquid chromatography mass spectrometry versus DOAC Dipstick, qualitative analysis of results | during urine collection and bioanalytical quantification, any time between August 2018 and April 2019 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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POC test, direct oral anticoagulants, apixaban, dabigatran, edoxaban, rivaroxaban, urine, LC-MS/MS, evaluation study, point of care test, blood coagulation, coagulation test, anticoagulant, thrombosis, pulmonary embolism, atrial fibrillation, anticoagulation, mass spectrometry