In Vitro Diagnostic Test for DOAC in Urine (PADOASU)

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

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]"

Study Overview

• Status: Completed
• Conditions: Anticoagulant Therapy
• Intervention / Treatment: Diagnostic test: DOAC Dipstick

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 Type: Observational
• Enrollment (Actual): 880

Contacts and Locations

Study Locations

• Germany
  • Bad Krozingen, Germany, 79189
    • Universitätsherzzentrum Bad Krozingen, Klinik für Kardiologie und Angiologie II
  • Bad Oeynhausen, Germany, 32545
    • Herz- und Diabeteszentrum NRW, Klinik für Kardiologie
  • Berlin, Germany, 12351
    • Vivantes Klinikum Neukölln
  • Berlin, Germany, 10249
    • Vivantes Klinikum im Friedrichshain
  • Berlin, Germany, 10789
    • Gerinnungszentrum Sucker
  • Coburg, Germany, 96450
    • Klinikum Coburg GmbH, II. Medizinische Klinik
  • Darmstadt, Germany, 64283
    • Klinikum Darmstadt - Gefäßzentrum
  • Dessau, Germany, 06846
    • Praxis Innere Medizin, Kardiologie und Angiologie
  • Dresden, Germany, 01067
    • Städtisches Klinikum Dresden, II. Medizinische Klinik
  • Dresden, Germany, 01307
    • Medizinische Fakultät Carl Gustav Carus, Medizinische Klinik und Poliklinik I
  • Frankfurt, Germany, 60389
    • Cardioangiologisches Centrum Bethanien
  • Freiburg, Germany, 79106
    • Klinik für Kardiologie und Angiologie I
  • Hamburg, Germany, 20246
    • Universitätsklinikum Hamburg-Eppendorf, II. Medizinische Klinik und Poliklinik
  • Heidenheim, Germany, 89522
    • Kliniken Landkreis Heidenheim
  • Köln, Germany, 50678
    • Krankenhaus der Augustinerinnen gGmbH, Klinik für Kardiologie und internistische Intensivmedizin
  • Leipzig, Germany, 04289
    • Zentrum für Blutgerinnungsstörungen, MVZ Labor Dr. Reising-Ackermann und Kollegen
  • Siegen, Germany, 57072
    • Zentrum für Praevention und Rehabilitation
  • Stahnsdorf, Germany, 14532
    • Die Parkkardiologie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Patients on routine treatment with Apixaban, Dabigatran, Edoxaban, and Rivaroxaban since 1 week or longer, an age of >18 years and fulfilling none the exclusion criteria are eligible. The patients participating in this Performance Assessment will be recruited directly at the point of care, i.e., the respective outpatient care unit.

"publication Thromb Haemost. 2019 Nov 8. doi: 10.1055/s-0039-1700545. [Epub ahead of print]"

Description

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]"

Study Plan

How is the study designed?

Design Details

• Observational Models: Other
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	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: test strip for urine analysis"publication Thromb Haemost. 2019 Nov 8. doi: 10.1055/s-0039-1700545. [Epub ahead of print]"
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: test strip for urine analysis"publication Thromb Haemost. 2019 Nov 8. doi: 10.1055/s-0039-1700545. [Epub ahead of print]"

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Doasense GmbH
• Collaborators: 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

Publications and helpful links

General Publications

• Harenberg J, Du S, Wehling M, Zolfaghari S, Weiss C, Kramer 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.
• Du S, Weiss C, Christina G, Kramer S, Wehling M, Kramer 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, Kramer S, Weiss C, Kramer 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.
• 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.
• Harenberg J, Beyer-Westendorf J, Crowther M, Douxfils J, Elalamy I, Verhamme P, Bauersachs R, Hetjens S, Weiss C; Working Group Members. Accuracy of a Rapid Diagnostic Test for the Presence of Direct Oral Factor Xa or Thrombin Inhibitors in Urine-A Multicenter Trial. Thromb Haemost. 2020 Jan;120(1):132-140. doi: 10.1055/s-0039-1700545. Epub 2019 Nov 8.

Helpful Links

• Homepage DOASENSE GmbH

Study record dates

Study Major Dates

• Study Start (Actual): August 22, 2018
• Primary Completion (Actual): April 9, 2019
• Study Completion (Actual): June 5, 2019

Study Registration Dates

• First Submitted: June 8, 2017
• First Submitted That Met QC Criteria: June 8, 2017
• First Posted (Actual): June 9, 2017

Study Record Updates

• Last Update Posted (Actual): April 21, 2022
• Last Update Submitted That Met QC Criteria: March 28, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: atrial fibrillation; anticoagulant; urine; anticoagulation; pulmonary embolism; thrombosis; LC-MS/MS; rivaroxaban; apixaban; mass spectrometry; edoxaban; dabigatran; direct oral anticoagulants; evaluation study; point of care test; blood coagulation; coagulation test; POC test
• Other Study ID Numbers: DOA-CS-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Individual data of patients are collected during the study and stored centrally at DOASENSE GmbH Heidelberg, Germany. They will be shared with other researchers upon request.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No