PADOASU: In Vitro Diagnostic Test for DOAC in Urine

Sponsor
Doasense GmbH (Industry)
Overall Status
Completed
CT.gov ID
NCT03182829
Collaborator
Clinical Research Services, Mannheim, Germany (Other), Institute Medical Statistics, Medical Faculty Mannheim (Other), Medical Care Center Dr. Limbach and Colleagues, Heidelberg, Germany (Other)
880
Enrollment
20
Locations
9.4
Actual Duration (Months)
44
Patients Per Site
4.7
Patients Per Site Per Month

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 DiseaseIntervention/TreatmentPhase
  • 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 Design

Study Type:
Observational
Actual Enrollment :
880 participants
Observational Model:
Other
Time Perspective:
Prospective
Official Title:
Post Marketing Study of an in Vitro Diagnostic Test for Direct Oral Anticoagulants (Apixaban, Edoxaban, Rivaroxaban, Dabigatran) in Urine
Actual Study Start Date :
Aug 22, 2018
Actual Primary Completion Date :
Apr 9, 2019
Actual Study Completion Date :
Jun 5, 2019

Arms and Interventions

ArmIntervention/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]"
  • Outcome Measures

    Primary Outcome Measures

    1. 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

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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]"

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Universitätsherzzentrum Bad Krozingen, Klinik für Kardiologie und Angiologie IIBad KrozingenGermany79189
    2Herz- und Diabeteszentrum NRW, Klinik für KardiologieBad OeynhausenGermany32545
    3Vivantes Klinikum im FriedrichshainBerlinGermany10249
    4Gerinnungszentrum SuckerBerlinGermany10789
    5Vivantes Klinikum NeuköllnBerlinGermany12351
    6Klinikum Coburg GmbH, II. Medizinische KlinikCoburgGermany96450
    7Klinikum Darmstadt - GefäßzentrumDarmstadtGermany64283
    8Praxis Innere Medizin, Kardiologie und AngiologieDessauGermany06846
    9Städtisches Klinikum Dresden, II. Medizinische KlinikDresdenGermany01067
    10Medizinische Fakultät Carl Gustav Carus, Medizinische Klinik und Poliklinik IDresdenGermany01307
    11Cardioangiologisches Centrum BethanienFrankfurtGermany60389
    12Klinik für Kardiologie und Angiologie IFreiburgGermany79106
    13Justus-Liebig-Universität Gießen, Interdisziplinärer Schwerpunkt für HämostaseologieGießenGermany35392
    14Universitätsklinikum Hamburg-Eppendorf, II. Medizinische Klinik und PoliklinikHamburgGermany20246
    15Pneumonologische Schwerpunktpraxis Heidelberg, Privatpraxis HarenbergHeidelbergGermany69121
    16Kliniken Landkreis HeidenheimHeidenheimGermany89522
    17Krankenhaus der Augustinerinnen gGmbH, Klinik für Kardiologie und internistische IntensivmedizinKölnGermany50678
    18Zentrum für Blutgerinnungsstörungen, MVZ Labor Dr. Reising-Ackermann und KollegenLeipzigGermany04289
    19Zentrum für Praevention und RehabilitationSiegenGermany57072
    20Die ParkkardiologieStahnsdorfGermany14532

    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

    Responsible Party:
    Doasense GmbH
    ClinicalTrials.gov Identifier:
    NCT03182829
    Other Study ID Numbers:
    • DOA-CS-002
    First Posted:
    Jun 9, 2017
    Last Update Posted:
    May 4, 2021
    Last Verified:
    May 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Doasense GmbH

    Study Results

    Participant Flow

    Recruitment DetailsStart of study: 18.08.2018 End of study: 10.04.2019 18 centres
    Pre-assignment Detail
    Arm/Group TitleFactor Xa InhibitorThrombin Inhibitor
    Arm/Group DescriptionThe aim was to include 450 patients on stable treatment with apixaban, edoxaban and rivaroxabanThe aim was to include 450 patients on stable treatment with dabigatran
    Period Title: Overall Study
    STARTED467444
    COMPLETED451429
    NOT COMPLETED1615

    Baseline Characteristics

    Arm/Group TitleFactor Xa InhibitorThrombin InhibitorTotal
    Arm/Group DescriptionPatients on therapy with apixaban, edoxaban and rivaroxaban for at least 7 daysPatients on therapy with dabigatran for at least 7 daysTotal of all reporting groups
    Overall Participants451429880
    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

    1. Primary Outcome
    TitleAccuracy of Factor Xa and Thrombin Inhibitors Pads of DOAC Dipstick From Urine Samples
    DescriptionLiquid chromatography mass spectrometry versus DOAC Dipstick, qualitative analysis of results
    Time Frameduring urine collection and bioanalytical quantification, any time between August 2018 and April 2019

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleFactor Xa InhibitorThrombin Inhibitor
    Arm/Group DescriptionPatients on treatment with apixaban, edoxaban, rivaroxabanPatients treated with dabigatran
    Measure Participants451429
    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 Hypothesisp-Value<0.05
    Comments
    MethodChi-squared
    Comments
    Method of EstimationEstimation ParameterMean Difference (Final Values)
    Estimated Value100
    Confidence Interval (2-Sided) 95%
    90 to 100
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Other Statistical AnalysisFisher's exact test

    Adverse Events

    Time Frame2 hours
    Adverse Event Reporting Description Adverse Events were not routinely assessed
    Arm/Group TitleFactor Xa InhibitorThrombin Inhibitor
    Arm/Group DescriptionPatients on treatment with apxiban, edoxaban and rivaroxabanPatients on treatment with dabigatran
    All Cause Mortality
    Factor Xa InhibitorThrombin Inhibitor
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/0 (NaN) 0/0 (NaN)
    Serious Adverse Events
    Factor Xa InhibitorThrombin Inhibitor
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/0 (NaN) 0/0 (NaN)
    Other (Not Including Serious) Adverse Events
    Factor Xa InhibitorThrombin Inhibitor
    Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
    Total0/0 (NaN) 0/0 (NaN)

    Limitations/Caveats

    [Not Specified]

    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/TitleHarenberg, Job Prof Dr.
    OrganizationDOASENSE GmbH
    Phone+496221825 ext 9785
    Emailj.harenberg@doasense.de
    Responsible Party:
    Doasense GmbH
    ClinicalTrials.gov Identifier:
    NCT03182829
    Other Study ID Numbers:
    • DOA-CS-002
    First Posted:
    Jun 9, 2017
    Last Update Posted:
    May 4, 2021
    Last Verified:
    May 1, 2021