Clinical trial NCT03182829: In Vitro Diagnostic Test for DOAC in Urine
Official title: Post Marketing Study of an in Vitro Diagnostic Test for Direct Oral Anticoagulants (Apixaban, Edoxaban, Rivaroxaban, Dabigatran) in Urine
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Anticoagulant Therapy
Keywords: 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
POC test
Lead sponsor: Doasense GmbH
Sponsor class: INDUSTRY
Collaborators: name: CRS Clinical Research Services Mannheim GmbH
name: Heidelberg University
name: Medical Care Center Dr. Limbach and Colleagues, Heidelberg, Germany
First posted: 2017-06-09
Enrollment: 880
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: OTHER
Time perspective: PROSPECTIVE
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. \[Epub ahead of print\]"

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. \[Epub ahead of print\]"

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. \[Epub ahead of print\]"

Eligibility 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.
* Patients in the end-stage of a severe disease.

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

Primary outcomes:
measure: Accuracy of Factor Xa and Thrombin Inhibitors Pads of DOAC Dipstick From Urine Samples
timeFrame: during urine collection and bioanalytical quantification, any time between August 2018 and April 2019
Secondary outcomes:
Other outcomes:
Locations:
city: Bad Krozingen
country: Germany
facility: Universitätsherzzentrum Bad Krozingen, Klinik für Kardiologie und Angiologie II
city: Bad Oeynhausen
country: Germany
facility: Herz- und Diabeteszentrum NRW, Klinik für Kardiologie
city: Berlin
country: Germany
facility: Vivantes Klinikum im Friedrichshain
city: Berlin
country: Germany
facility: Gerinnungszentrum Sucker
city: Berlin
country: Germany
facility: Vivantes Klinikum Neukölln
city: Coburg
country: Germany
facility: Klinikum Coburg GmbH, II. Medizinische Klinik
city: Darmstadt
country: Germany
facility: Klinikum Darmstadt - Gefäßzentrum
city: Dessau
country: Germany
facility: Praxis Innere Medizin, Kardiologie und Angiologie
city: Dresden
country: Germany
facility: Städtisches Klinikum Dresden, II. Medizinische Klinik
city: Dresden
country: Germany
facility: Medizinische Fakultät Carl Gustav Carus, Medizinische Klinik und Poliklinik I
city: Frankfurt
country: Germany
facility: Cardioangiologisches Centrum Bethanien
city: Freiburg
country: Germany
facility: Klinik für Kardiologie und Angiologie I
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf, II. Medizinische Klinik und Poliklinik
city: Heidenheim
country: Germany
facility: Kliniken Landkreis Heidenheim
city: Köln
country: Germany
facility: Krankenhaus der Augustinerinnen gGmbH, Klinik für Kardiologie und internistische Intensivmedizin
city: Leipzig
country: Germany
facility: Zentrum für Blutgerinnungsstörungen, MVZ Labor Dr. Reising-Ackermann und Kollegen
city: Siegen
country: Germany
facility: Zentrum für Praevention und Rehabilitation
city: Stahnsdorf
country: Germany
facility: Die Parkkardiologie
Study officials:
affiliation: Pneumonologische Schwerpunktpraxis Heidelberg, Privatpraxis Harenberg
name: Job Harenberg, Professor
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.